Hetrocyclic compounds that are inhibitors of the enzyme DPP-IV

ABSTRACT

The present invention relates to therapeutically active and selective inhibitors of the enzyme DPP-IV, pharmaceutical compositions comprising the compounds and the use of such compounds for and the manufacture of medicaments for treating diseases that are associated with proteins that are subject to inactivation by DPP-IV, such as type 2 diabetes and obesity. The present inhibitors are novel purine derivatives, attached at position 8 of the purine skeleton to a diamine.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of application serial no.PCT/DK02/00608 filed on Sep. 19, 2002 and claims priority under 35U.S.C. 119 of Danish application no. PA 2001 01358 filed on Sep. 24,2001, and U.S. provisional application No. 60/324,574 filed on Sep. 24,2001, the contents of all of which are fully incorporated herein byreference.

FIELD OF THE INVENTION

[0002] The present invention relates to therapeutically active andselective inhibitors of the enzyme DPP-IV, pharmaceutical compositionscomprising the compounds and the use of such compounds for and themanufacture of medicaments for treating diseases that are associatedwith proteins that are subject to inactivation by DPP-IV, such as type 2diabetes and obesity.

BACKGROUND OF THE INVENTION

[0003] Dipeptidyl peptidase-IV (DPP-IV), a serine protease belonging tothe group of post-proline/alanine cleaving amino-dipeptidases,specifically removes the two N-terminal amino acids from proteins havingproline or alanine in position 2.

[0004] Although the physiological role of DPP-IV has not been completelyestablished, it is believed to play an important role in neuropeptidemetabolism, T-cell activation, gastric ulceration, functional dyspepsia,obesity, appetite regulation, impaired fasting glucose (IFG) anddiabetes.

[0005] DPP-IV has been implicated in the control of glucose metabolismbecause its substrates include the insulinotropic hormones Glucagon likepeptide-1 (GLP-1) and Gastric inhibitory peptide (GIP). GLP-1 and GIPare active only in their intact forms; removal of their two N-terminalamino acids inactivates them.

[0006] In vivo administration of synthetic inhibitors of DPP-IV preventsN-terminal degradation of GLP-1 and GIP, resulting in higher plasmaconcentrations of these hormones, increased insulin secretion and,therefore, improved glucose tolerance. Therefore, such inhibitors havebeen proposed for the treatment of patients with Type 2 diabetes, adisease characterised by decreased glucose tolerance. (Hoist, J. J.;Deacon, C. F. Diabetes 47 (1998) 1663-70) Diabetic dyslipidemia ischaracterized by multiple lipoprotein defects, including moderately highserum levels of cholesterol and triglycerides, small LDL particles, andlow levels of HDL cholesterol. The results of recent clinical trialsreveal beneficial effects of cholesterol-lowering therapy in diabeticand non-diabetic patients, thus supporting increased emphasis ontreatment of diabetic dyslipidemia. The National Cholesterol EducationProgram's Adult Treatment Panel II advocated this need for intensivetreatment of diabetic dyslipidemia. Obesity is a well-known risk factorfor the development of many very common diseases such asatherosclerosis, hypertension and diabetes. The incidence of obesepeople and thereby also these diseases is increasing throughout theentire industrialised world. Except for exercise, diet and foodrestriction no convincing pharmacological treatment for reducing bodyweight effectively and acceptably currently exist. However, due to itsindirect but important effect as a risk factor in mortal and commondiseases it will be important to find treatment for obesity or appetiteregulation. Even mild obesity increases the risk for premature death,diabetes, hypertension, atherosclerosis, gallbladder disease and certaintypes of cancer. In the industrialised western world the prevalence ofobesity has increased significantly in the past few decades. Because ofthe high prevalence of obesity and its health consequences, itsprevention and treatment should be a high public health priority.

[0007] At present a variety of techniques are available to effectinitial weight loss. Unfortunately, initial weight loss is not anoptimal therapeutic goal. Rather, the problem is that most obesepatients eventually regain their weight. An effective means to establishand/or sustain weight loss is the major challenge in the treatment ofobesity today.

[0008] Several compounds have been shown to inhibit DPP-IV, but all ofthese have limitations in relation to the potency, stability,selectivity, toxicity, and pharmacodynamic properties. Thus, there is aneed for the provision of DPP-IV inhibitors that are superior withrespect to one or more of the above listed properties, and which will beuseful for the treatment of conditions, which may be regulated ornormalised by inhibition of DPP-IV.

SUMMARY OF THE INVENTION

[0009] The present invention consists of novel purine derivatives,attached at position 8 of the purine skeleton to a diamine. Thecompounds of the present invention are thus not amino acid derivatives,such as the presently known DPP-IV inhibitors, but consist of structuralelements hitherto unrelated to DPP-IV inhibition, and as such theyrepresent novel solutions to the problem of finding an optimal DPP-IVinhibitor. These compounds are potent and selective inhibitors ofDPP-IV, and are effective in treating conditions that may be regulatedor normalised via inhibition of DPP-IV. The invention also concernsmethods for preparing the compounds, pharmaceutical compositionscomprising the compounds, a method of inhibiting DPP-IV comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount thereof, the compounds for use as a pharmaceutical, andtheir use in a process for the preparation of a medicament for treatinga condition which may be regulated or normalised via inhibition ofDPP-IV.

[0010] Definitions

[0011] The term “DPP-IV” as used herein is intended to mean Dipeptidylpeptidase IV (EC 3.4.14.5; DPP-IV), also known as CD26. DPP-IV cleaves adipeptide from the N terminus of a polypeptide chain containing aproline or alanine residue in the penultimate position.

[0012] The term “treatment” is defined as the management and care of apatient for the purpose of combating the disease, condition, or disorderand includes the administration of a compound of the present inventionto prevent the onset of the symptoms or complications, or alleviatingthe symptoms or complications, or eliminating the disease, condition, ordisorder.

[0013] The term “beta cell degeneration” is intended to mean loss ofbeta cell function, beta cell dysfunction, and death of beta cells, suchas necrosis or apoptosis of beta cells.

[0014] The term “alkyl” as used herein, alone or in combination, refersto a straight or branched, saturated hydrocarbon chain having theindicated number of carbon atoms. Similarly the term “alkylene” refersto the corresponding bivalent radical having the indicated number ofcarbon atoms.

[0015] Non-limiting examples of such saturated hydrocarbons are e.g.methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec. Butyl, isobutyl,tert. Butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl,4-methylpentyl, neopentyl, 2,2-dimethylpropyl and the like.

[0016] The term “alkenyl” used herein, alone or in combination, refersto a straight or branched, unsaturated hydrocarbon chain having theindicated number of carbon atoms and at least one double bond. Similarlythe term “alkenylene” refers to the corresponding bivalent radicalhaving the indicated number of carbon atoms. Non-limiting examples ofsuch unsaturated hydrocarbons are vinyl, 1-propenyl, allyl, isopropenyl,n-butenyl, n-pentenyl and n-hexenyl and the like.

[0017] The term “alkynyl” as used herein, alone or in combination,refers to an unsaturated hydrocarbon chain having the indicated numberof carbon atoms and at least one triple bond such as but not limited to—C≡CH, —C≡CCH₃, —CH₂C≡CH, —CH₂—CH₂—C≡CH, —CH(CH₃)C≡CH and the like.

[0018] The term “cycloalkyl” as used herein refers to a radical of oneor more saturated cyclic hydrocarbon having the indicated number ofcarbon atoms. Similarly the term “cycloalkylene” refers to thecorresponding bivalent radical having the indicated number of carbonatoms. Non-limiting examples of such saturated cyclic hydrocarbons arecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl and thelike.

[0019] The term “cycloheteroalkyl” as used herein refers to a radical oftotally saturated heterocycle having the indicated number of carbonatoms like a cyclic hydrocarbon containing one or more heteroatomsselected from nitrogen, oxygen and sulphur independently in the cycle.Similarly the term “cycloheteroalkylene” refers to the correspondingbivalent radical having the indicated number of carbon atoms like acyclic hydrocarbon containing one or more heteroatoms selected fromnitrogen, oxygen and sulphur independently in the cycle.

[0020] Non-limiting examples of such saturated heterocycles arepyrrolidine (1-pyrrolidine; 2-pyrrolidine; 3-pyrrolidine; 4-pyrrolidine;5-pyrrolidine); pyrazolidine (1-pyrazolidine; 2-pyrazolidine;3-pyrazolidine; 4-pyrazolidine; 5-pyrazolidine); imidazolidine(1-imidazolidine; 2-imidazolidine; 3-imidazolidine; 4-imidazolidine;5-imidazolidine); thiazolidine (2-thiazolidine; 3-thiazolidine;4-thiazolidine; 5-thiazolidine); piperidine (1-piperidine; 2-piperidine;3-piperidine; 4-piperidine; 5-piperidine; 6-piperidine); piperazine(1-piperazine; 2-piperazine; 3-piperazine; 4-piperazine; 5-piperazine;6-piperazine); morpholine (2-morpholine; 3-morpholine; 4-morpholine;5-morpholine; 6-morpholine); thiomorpholine (2-thiomorpholine;3-thiomorpholine; 4-thiomorpholine; 5-thiomorpholine; 6-thiomorpholine);1,2-oxathiolane (3-(1,2-oxathiolane); 4-(1,2-oxathiolane);5-(1,2-oxathiolane); 1,3-dioxolane (2-(1,3-dioxolane);4-(1,3-dioxolane); 5-(1,3-dioxolane); tetrahydropyrane;(2-tetrahydropyrane; 3-tetrahydropyrane; 4-tetrahydropyrane;5-tetrahydropyrane; 6-tetrahydropyrane); hexahydropyridazine(1-(hexahydropyridazine); 2-(hexahydropyridazine);3-(hexahydropyridazine); 4-(hexahydropyridazine);5-(hexahydropyridazine); 6-(hexahydropyridazine)). Similarly the term“cycloheteroalkylene” refers to the corresponding bivalent radicalhaving the indicated number of carbon atoms like a cyclic hydrocarboncontaining one or more heteroatoms selected from nitrogen, oxygen andsulphur independently in the cycle.

[0021] The term “aryl” as used herein includes carbocyclic aromatic ringsystems. Aryl is also intended to include the partially hydrogenatedderivatives of the carbocyclic systems. Similarly the term “arylene”refers to the corresponding bivalent radical.

[0022] The term “heteroaryl” as used herein includes heterocyclicunsaturated ring systems containing one or more heteroatoms selectedfrom nitrogen, oxygen and sulphur. Similarly the term“heteroarylenearylene” refers to the corresponding bivalent radical.

[0023] Non-limiting examples of such unsaturated ring systems containingone or more heteroatoms are furyl, thienyl, pyrrolyl. The term“heteroaryl” is also intended to include the partially hydrogenatedderivatives of the heterocyclic systems enumerated below.

[0024] The terms “aryl” and “heteroaryl” as used herein refers to anaryl which can be optionally substituted or a heteroaryl which can beoptionally substituted and includes phenyl, biphenyl, indenyl, naphthyl(1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl,N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl,3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl,3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl,xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl(2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl(1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl,1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl),thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl,3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl,4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl(1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl(2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl,5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl),2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl),3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl),5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl),7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl(2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl,5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl),2,3-dihydro-benzo[b]thiophenyl (2-(2,3-dihydrobenzo[b]thiophenyl),3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl),5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl),7-(2,3-dihydrobenzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl,3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole(1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl,7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl,4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl,8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl),benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl,5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl(1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl),5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl,5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl,5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl),10,11-dihydro-5H-dibenz[b,f]azepine(10,11-dihydro-5H-dibenz[b,f]azepine-1-yl,10,11-dihydro-5H-dibenz[b,f]azepine-2-yl,10,11-dihydro-5H-dibenz[b,f]azepine-3-yl,10,11-dihydro-5H-dibenz[b,f]azepine-4-yl,10,11-dihydro-5H-dibenz[b,f]azepine-5-yl).

[0025] The term “halogen” as used herein refers to fluoro, chloro,bromo, and iodo.

[0026] The term “arylene-alkylene” as used herein refers to an “arylene”group as defined above attached through an “alkylene” group as definedabove having the indicated number of carbon atoms. Similarly the term“alkylene-arylene” as used herein refers to an “alkylene” group asdefined above having the indicated number of carbon atoms attachedthrough an “arylene” group as defined above.

[0027] The term “alkylene-arylene-alkylene” refers to a“arylene-alkylene” group as defined above connected through an“alkylene” group as defined above having the indicated number of carbonatoms.

[0028] The term “heteroaryl-alkylene” as used herein refers to a“heteroaryl” group as defined above attached through an “alkylene” groupas defined above having the indicated number of carbon atoms.

[0029] The term “cycloalkyl-alkylene” as used herein refers to a“cycloalkyl” group as defined above having the indicated number ofcarbon atoms attached through an “alkylene” group as defined abovehaving the indicated number of carbon atoms.

[0030] The term “cycloheteroalkyl-alkylene” as used herein refers to a“cycloheteroalkyl” group as defined above having the indicated number ofcarbon atoms attached through an “alkylene” group as defined abovehaving the indicated number of carbon atoms.

DESCRIPTION OF THE INVENTION

[0031] The present invention provides compounds of formula I

[0032] A is C₂-C₆ alkylene; C₂-C₁₀ alkenylene; C₃-C₇ cycloalkylene;C₃-C₇ cycloheteroalkylene; arylene; heteroarylene; C₁-C₂alkylene-arylene; arylene-C₁-C₂ alkylene; C₁-C₂ alkylene-arylene-C₁-C₂alkylene, wherein each alkylene, alkenylene, cycloalkylene,cycloheteroalkylene, arylene, or heteroarylene is optionally substitutedwith one or more R³ independently;

[0033] R¹ is aryl optionally substituted with one or more R²independently or heteroaryl optionally substituted with one or more R²independently;

[0034] R² is H; C₁-C₇ alkyl; C₂-C₇ alkenyl; C₂-C₇ alkynyl; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; —NHCOR³; —NHSO₂R³; —SR³; —SOR³;—SO₂R³; —OCOR³; —CO₂R⁴; —CON(R⁴)₂; —CSN(R⁴)₂; —NHCON(R⁴)₂; —NHCSN(R⁴)₂;—NHCONNH₂; —SO₂N(R⁴)₂; —OR⁴; cyano; nitro; halogen, wherein each alkyl,alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is optionallysubstituted with one or more R³ independently;

[0035] R³ is C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₂-C₁₀ alkynyl; C₃-C₇cycloalkyl; aryl; heteroaryl; OR¹⁰; N(R¹⁰)₂; SR¹⁰, wherein each alkyl,alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl is optionallysubstituted with one or more R¹⁰ independently;

[0036] R⁴ is H; C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₂-C₁₀ alkynyl; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; aryl-C₁-C₅ alkylene;heteroaryl; heteroaryl-C₁-C₅alkylene, wherein each alkyl, alkenyl,alkynyl, cycloalkyl, cycloheteroalkyl, aryl, aryl-C₁-C₅ alkylene,heteroaryl, and heteroaryl-C₁-C₅ alkylene is optionally substituted withone or more R¹⁰ independently;

[0037] R⁵ is H; C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₂-C₁₀ alkynyl; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; heteroaryl; —OR⁷;—[(CH₂)_(o)—O]_(p)—C₁-C₅alkyl, wherein o and p are 1-3 independently,and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl,aryl, and heteroaryl is optionally substituted with one or more R⁷independently;

[0038] R⁶ is H; C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₂-C₁₀ alkynyl; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; heteroaryl; aryl-C₁-C₅alkylene; heteroaryl-C₁-C₅ alkylene; C₃-C₇ cycloheteroalkyl-C₁-C₅alkylene, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloheteroalkyl, C₃-C₇ cycloheteroalkyl-C₁-C₅ alkylene, aryl,aryl-C₁-C₅ alkylene, heteroaryl, aryl-C₁-C₅ alkylene, andheteroaryl-C₁-C₅ alkylene is optionally substituted with one or more R¹⁰independently;

[0039] R⁷ is H; ═O; C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₂-C₁₀ alkynyl; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; heteroaryl, OR¹⁰; N(R¹⁰)₂;SR¹⁰; cyano; hydroxy; halogen; —CF₃; —CCl₃; —OCF₃; or —OCH₃ wherein eachalkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, andheteroaryl is optionally substituted with one or more R¹⁰ independently;

[0040] R⁸ is H; C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₂-C₁₀ alkynyl; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; heteroaryl, OR¹⁰; N(R¹⁰)₂;SR¹⁰, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloheteroalkyl, aryl, and heteroaryl is optionally substituted withone or more R¹⁰ independently;

[0041] R⁹ is H; C₁-C₁₀ alkyl optionally substituted with one or more R⁸independently; or halogen;

[0042] R¹⁰ is H; —CF₃; —CCl₃; —OCF₃; —OCH₃; cyano; halogen; —OH, —COCH₃;—CONH₂; —CONHCH₃; —CON(CH₃)₂; —NO₂; —SO₂NH₂; or —SO₂N(CH₃)₂;

[0043] if two R⁴ or two R¹⁰ are attached to the same nitrogen they maybe connected to form a 3- to 7-membered ring;

[0044] R¹¹ is H; C₁-C₆ alkyl optionally substituted with one or more R³independently;

[0045] R¹² is H; C₁-C₆ alkyl optionally substituted with one or more R³independently; or

[0046] If A is C₃-C₇ cycloalkylene or C₃-C₇ cycloheteroalkylene R¹² maybe a valence bond between the nitrogen to which R¹² is attached and oneof the atoms in the cycloalkylene or cycloheteroalkylene;

[0047] or a salt thereof with a pharmaceutically acceptable acid orbase.

[0048] In another embodiment A is C₂-C₆ alkylene; C₂-C₁₀ alkenylene;C₃-C₇ cycloalkylene; C₃-C₇ cycloheteroalkylene; or arylene, wherein eachalkylene, alkenylene, cycloalkylene, cycloheteroalkylene, or arylene isoptionally substituted with one or more R³ independently;

[0049] In another embodiment A is C₃-C₇ cycloalkylene optionallysubstituted with one or more R³ independently.

[0050] In another embodiment A is cyclohexylene optionally substitutedwith one or more R³ independently.

[0051] In another embodiment A is cyclohexylene.

[0052] In another embodiment R¹ is aryl optionally substituted with oneor more R² independently.

[0053] In another embodiment R¹ is phenyl optionally substituted withone or more R² independently.

[0054] In another embodiment R₂ is C₁-C₇ alkyl; C₂-C₇ alkynyl; cyano; orhalogen, wherein each alkyl and alkynyl is optionally substituted withone or more R³ independently.

[0055] In another embodiment R₂ is C₁-C₇ alkyl; C₂-C₇ alkynyl; cyano; orhalogen.

[0056] In another embodiment R₂ is halogen.

[0057] In another embodiment R³ is C₁-C₁₀ alkyl or aryl, wherein eachalkyl or aryl is substituted with one or more R¹⁰ independently.

[0058] In another embodiment R³ is C₁-C₁₀ alkyl or aryl.

[0059] In another embodiment R³ is methyl or phenyl.

[0060] In another embodiment R⁴ is H; C₁-C₁₀ alkyl or aryl, wherein eachalkyl or aryl is substituted with one or more R¹⁰ independently.

[0061] In another embodiment R⁴ is H; C₁-C₁₀ alkyl or aryl.

[0062] In another embodiment R⁴ is H, methyl or phenyl.

[0063] In another embodiment R⁵ is H; C₁-C₁₀ alkyl; aryl-C₁-C₅ alkylene;or heteroaryl-C₁-C₅ alkylene, wherein each alkyl, aryl-C₁-C₅ alkyleneand heteroaryl-C₁-C₅ alkylene is optionally substituted with one or moreR⁷ independently.

[0064] In another embodiment R⁵ is H; C₁-C₁₀ alkyl optionallysubstituted with one or more R⁷ independently; or C₂-C₁₀ alkenyloptionally substituted with one or more R⁷ independently.

[0065] In another embodiment R⁵ is H or C₁-C₁₀ alkyl optionallysubstituted with one or more R⁷ independently.

[0066] In another embodiment R⁵ is H.

[0067] In another embodiment R⁵ is methyl or ethyl optionallysubstituted with one or more R⁷ independently.

[0068] In another embodiment R⁶ is C₁-C₁₀ alkyl; aryl-C₁-C₅ alkylene; orheteroaryl-C₁-C₅ alkylene, wherein each alkyl, aryl-C₁-C₅ alkylene andheteroaryl-C₁-C₅ alkylene is optionally substituted with one or more R¹⁰independently.

[0069] In another embodiment R⁶ is C₁-C₁₀ alkyl; aryl-C₁-C₅ alkylene; orheteroaryl-C₁-C₅ alkylene.

[0070] In another embodiment R⁶ is C₁-C₁₀ alkyl optionally substitutedwith one or more R¹⁰ independently.

[0071] In another embodiment R⁶ is C₁-C₁₀ alkyl.

[0072] In another embodiment R⁶ is methyl or ethyl optionallysubstituted by one or more R¹⁰ independently.

[0073] In another embodiment R⁷ is H; ═O; C₁-C₁₀ alkyl; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; heteroaryl, OR¹⁰; N(R¹⁰)₂;SR¹⁰, wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl, andheteroaryl is optionally substituted with one or more R¹⁰ independently.

[0074] In another embodiment R⁷ is ═O; C₃-C₇ cycloalkyl; C₃-C₇cycloheteroalkyl; aryl; or heteroaryl, wherein each cycloalkyl,cycloheteroalkyl, aryl, and heteroaryl is optionally substituted withone or more R¹⁰ independently.

[0075] In another embodiment R⁷ is ═O; C₃-C₇ cycloalkyl optionallysubstituted with one or more R¹⁰ independently or aryl optionallysubstituted with one or more R¹⁰ independently.

[0076] In another embodiment R⁷ is ═O or aryl optionally substitutedwith one or more R¹⁰ independently.

[0077] In another embodiment R⁷ is ═O or phenyl optionally substitutedby one or more R¹⁰ independently.

[0078] In another embodiment R⁸ is aryl or heteroaryl, wherein each aryland heteroaryl is optionally substituted with one or more R¹⁰independently.

[0079] In another embodiment R⁸ is aryl or heteroaryl.

[0080] In another embodiment R⁸ is phenyl.

[0081] In another embodiment R⁹ is H; C₁-C₁₀ alkyl; or halogen.

[0082] In another embodiment R⁹ is H.

[0083] In another embodiment R¹⁰ is H; —CF₃; —OH; cyano; halogen; —OCF₃;or —OCH₃.

[0084] In another embodiment R¹⁰ is H; cyano; halogen; or —OCH₃.

[0085] In another embodiment R¹¹ is H.

[0086] In another embodiment R¹² is H.

[0087] In another embodiment the invention provides compounds of thegeneral formula II

[0088] A is C₂-C₆ alkylene; C₂-C₁₀ alkenylene; C₃-C₇ cycloalkylene;C₃-C₇ cycloheteroalkylene; arylene; heteroarylene; C₁-C₂alkylene-arylene; arylene-C₁-C₂ alkylene; C₁-C₂ alkylene-arylene-C₁-C₂alkylene, wherein each alkylene, alkenylene, cycloalkylene,cycloheteroalkylene, arylene, or heteroarylene is optionally substitutedwith one or more R³ independently;

[0089] R¹ is aryl optionally substituted with one or more R²independently or heteroaryl optionally substituted with one or more R²independently;

[0090] R² is H; C₁-C₇ alkyl; C₂-C₇ alkenyl; C₂-C₇ alkynyl; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; —NHCOR³; —NHSO₂R³; —SR³; —SOR³;—SO₂R³; —OCOR³; —CO₂R⁴; —CON(R⁴)₂; —CSN(R⁴)₂; —NHCON(R⁴)₂; —NHCSN(R⁴)₂;—NHCONNH₂; —SO₂N(R⁴)₂; —OR⁴; cyano; —CF₃; nitro; halogen, wherein eachalkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is optionallysubstituted with one or more R³ independently;

[0091] R³ is C₁-C₁₀ alkyl; C₂-C₁₁ alkenyl; C₂-C₁₁ alkynyl; C₃-C₇cycloalkyl; aryl; heteroaryl; OR¹⁰; N(R¹⁰)₂; SR¹⁰, wherein each alkyl,alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl is optionallysubstituted with one or more R¹⁰ independently;

[0092] R⁴ is H; C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₂-C₁₀ alkynyl; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; aryl-C₁-C₅ alkylene;heteroaryl; heteroaryl-C₁-C₅alkylene, —CF₃ or —CHF₂, wherein each alkyl,alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, aryl-C₁-C₅alkylene, heteroaryl, and heteroaryl-C₁-C₅ alkylene is optionallysubstituted with one or more R¹⁰ independently;

[0093] R⁵ is H; C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₂-C₁₀ alkynyl; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; heteroaryl; —OR⁷;aryl-C₁-C₅alkylene; heteroaryl-C₁-C₅alkylene; —C₁-C₅-alkyl-C(═O)-aryl,—C₁-C₅-alkyl-C(═O)-heteroaryl or —[(CH₂)_(o)—O]_(p)—C₁-C₅ alkyl; whereino and p are 1-3 independently, and wherein each alkyl, alkenyl, alkynyl,cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, aryl-C₁-C₅ alkylene;—C₁-C₅-alkyl-C(═O)-aryl, —C₁-C₅-alkyl-C(═O)-heteroaryl andheteroaryl-C₁-C₅ alkylene is optionally substituted with one or more R⁷independently;

[0094] R⁶ is H; C₁-C₁₀ alkyl; C₂-C₁₀alkenyl; C₂-C₁₀alkynyl; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; heteroaryl; aryl-C₁-C₅alkylene; heteroaryl-C₁-C₅ alkylene; C₃-C₇ cycloheteroalkyl-C₁-C₅alkylene, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloheteroalkyl, C₃-C₇ cycloheteroalkyl-C₁-C₅ alkylene, aryl,heteroaryl, aryl-C₁-C₅ alkylene, and heteroaryl-C₁-C₅ alkylene isoptionally substituted with one or more R¹⁰ independently;

[0095] R⁷ is H; ═O; C₁-C₁₀ alkyl; C₂-C₁₀alkenyl; C₂-C₁₀alkynyl; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; heteroaryl, OR¹⁰; N(R¹⁰)₂;SR¹⁰; cyano; hydroxy; halogen; —CF₃; —CCl₃; —OCF₃; or —OCH₃ wherein eachalkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, andheteroaryl is optionally substituted with one or more R¹⁰ independently;

[0096] R⁸ is H; C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₂-C₁₀ alkynyl; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; heteroaryl, OR¹⁰; N(R¹⁰)₂;SR¹⁰, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloheteroalkyl, aryl, and heteroaryl is optionally substituted withone or more R¹⁰ independently;

[0097] R⁹ is H; C₁-C₁₀ alkyl optionally substituted with one or more R⁸independently; or halogen;

[0098] R¹⁰ is H; —CF₃; —CCl₃; —OCF₃; —OCH₃; cyano; halogen; —OH, —COCH₃;—CONH₂; —CONHCH₃; —CON(CH₃)₂; —NO₂; —SO₂NH₂; or —SO₂N(CH₃)₂;

[0099] if two R⁴ or two R¹⁰ are attached to the same nitrogen they maybe connected to form a 3- to 7-membered ring;

[0100] R¹¹ is H; C₁-C₆ alkyl optionally substituted with one or more R³independently;

[0101] R¹² is H; C₁-C₆ alkyl optionally substituted with one or more R³independently; or

[0102] If A is C₃-C₇ cycloalkylene or C₃-C₇ cycloheteroalkylene R¹² maybe a valence bond between the nitrogen to which R¹² is attached and oneof the atoms in the cycloalkylene or cycloheteroalkylene;

[0103] or a salt thereof with a pharmaceutically acceptable acid orbase.

[0104] In another embodiment A is C₂-C₆ alkylene; C₂-C₁₀ alkenylene;C₃-C₇ cycloalkylene; C₃-C₇ cycloheteroalkylene; or arylene, wherein eachalkylene, alkenylene, cycloalkylene, cycloheteroalkylene, or arylene isoptionally substituted with one or more R³ independently;

[0105] In another embodiment A is C₂-C₆ alkylene; C₂-C₁₀ alkenylene;C₃-C₇ cycloalkylene; C₃-C₇ cycloheteroalkylene; arylene; heteroarylene;C₁-C₂ alkylene-arylene; arylene-C₁-C₂ alkylene; C₁-C₂alkylene-arylene-C₁-C₂ alkylene, wherein each alkylene, alkenylene,cycloalkylene, cycloheteroalkylene, arylene, or heteroarylene isoptionally substituted with one or more R³ independently;

[0106] R¹ is aryl optionally substituted with one or more R²independently or heteroaryl optionally substituted with one or more R²independently;

[0107] R² is H; C₁-C₇ alkyl; C₂-C₇ alkenyl; C₂-C₇ alkynyl; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; —NHCOR³; —NHSO₂R³; —SR³; —SOR³;—SO₂R³; —OCOR³; —CO₂R⁴; —CON(R⁴)₂; —CSN(R⁴)₂; —NHCON(R⁴)₂; —NHCSN(R⁴)₂;—NHCONNH₂; —SO₂N(R⁴)₂; —OR⁴; cyano; nitro; halogen, wherein each alkyl,alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is optionallysubstituted with one or more R³ independently;

[0108] R³ is C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₂-C₁₀ alkynyl; C₃-C₇cycloalkyl; aryl; heteroaryl; OR¹⁰; N(R¹⁰)₂; SR¹⁰, wherein each alkyl,alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl is optionallysubstituted with one or more R¹⁰ independently;

[0109] R⁴ is H; C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₂-C₁₀ alkynyl; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; aryl-C₁-C₅ alkylene;heteroaryl; heteroaryl-C₁-C₅ alkylene, wherein each alkyl, alkenyl,alkynyl, cycloalkyl, cycloheteroalkyl, aryl, aryl-C₁-C₅ alkylene,heteroaryl, and heteroaryl-C₁-C₅ alkylene is optionally substituted withone or more R¹⁰ independently;

[0110] R⁵ is H; C₁-C₁₀alkyl; C₂-C₁₀alkenyl; C₂-C₁₀ alkynyl; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; heteroaryl; —OR⁷;—[(CH₂)_(o)—O]_(p)—C₁-C₅ alkyl, wherein o and p are 1-3 independently,and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl,aryl, and heteroaryl is optionally substituted with one or more R⁷independently;

[0111] R⁶ is H; C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₂-C₁₀ alkynyl; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; heteroaryl; aryl-C₁-C₅alkylene; heteroaryl-C₁-C₅ alkylene; C₃-C₇ cycloheteroalkyl-C₁-C₅alkylene, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloheteroalkyl, C₃-C₇ cycloheteroalkyl-C₁-C₅ alkylene, aryl,aryl-C₁-C₅ alkylene, heteroaryl, aryl-C₁-C₅ alkylene, andheteroaryl-C₁-C₅ alkylene is optionally substituted with one or more R¹⁰independently;

[0112] R⁷ is H; ═O; C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₂-C₁₀ alkynyl; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; heteroaryl, OR¹⁰; N(R¹⁰)₂;SR¹⁰; cyano; hydroxy; halogen; —CF₃; —CCl₃; —OCF₃; or —OCH₃ wherein eachalkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, andheteroaryl is optionally substituted with one or more R¹⁰ independently;

[0113] R⁸ is H; C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₂-C₁₀ alkynyl; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; heteroaryl, OR¹⁰; N(R¹⁰)₂;SR¹⁰, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloheteroalkyl, aryl, and heteroaryl is optionally substituted withone or more R¹⁰ independently;

[0114] R⁹ is H; C₁-C₁₀ alkyl optionally substituted with one or more R⁸independently; or halogen;

[0115] R¹⁰ is H; —CF₃; —CCl₃; —OCF₃; —OCH₃; cyano; halogen; —OH, —COCH₃;—CONH₂; —CONHCH₃; —CON(CH₃)₂; —NO₂; —SO₂NH₂; or —SO₂N(CH₃)₂;

[0116] if two R⁴ or two R¹⁰ are attached to the same nitrogen they maybe connected to form a 3- to 7-membered ring;

[0117] R¹¹ is H; C₁-C₆ alkyl optionally substituted with one or more R³independently;

[0118] R¹² is H; C₁-C₆ alkyl optionally substituted with one or more R³independently; or

[0119] If A is C₃-C₇ cycloalkylene or C₃-C₇ cycloheteroalkylene R¹² maybe a valence bond between the nitrogen to which R¹² is attached and oneof the atoms in the cycloalkylene or cycloheteroalkylene;

[0120] or a salt thereof with a pharmaceutically acceptable acid or base

[0121] In another embodiment A is C₃-C₇ cycloalkylene optionallysubstituted with one or more R³ independently.

[0122] In another embodiment A is cyclohexylene or cycloheptylene, eachoptionally substituted with one or more R³ independently.

[0123] In another embodiment A is cyclohexylene optionally substitutedwith one or more R³ independently

[0124] In another embodiment A is cyclohexylene or cycloheptylene.

[0125] In another embodiment A is cyclohexylene

[0126] In another embodiment A is

[0127] In another embodiment R¹ is aryl optionally substituted with oneor more R² independently.

[0128] In another embodiment R¹ is phenyl optionally substituted withone or more R² independently.

[0129] In another embodiment R₂ is C₁-C₇ alkyl; C₂-C₇ alkynyl;; —OR⁴;cyano; —CF₃; or halogen, wherein each alkyl and alkynyl is optionallysubstituted with one or more R³ independently.

[0130] In another embodiment R₂ is C₁-C₇ alkyl; C₂-C₇ alkynyl; cyano;—CF₃; or halogen.

[0131] In another embodiment R₂ is cyano, —CF₃ or halogen.

[0132] In another embodiment R₂ is C₁-C₇ alkyl; C₂-C₇ alkynyl; cyano; orhalogen, wherein each alkyl and alkynyl is optionally substituted withone or more R³ independently.

[0133] In another embodiment R₂ is C₁-C₇ alkyl; C₂-C₇ alkynyl; cyano; orhalogen.

[0134] In another embodiment R₂ is halogen.

[0135] In another embodiment R³ is C₁-C₁₀ alkyl or aryl, wherein eachalkyl or aryl is substituted with one or more R¹⁰ independently.

[0136] In another embodiment R³ is C₁-C₁₀ alkyl or aryl.

[0137] In another embodiment R³ is methyl or phenyl.

[0138] In another embodiment R⁴ is H; C₁-C₁₀ alkyl, —CHF₂, or aryl,wherein each alkyl or aryl is substituted with one or more R¹⁰independently.

[0139] In another embodiment R⁴ is H; C₁-C₁₀ alkyl, —CHF₂, or aryl.

[0140] In another embodiment R⁴ is H, —CHF₂, methyl or phenyl.

[0141] In another embodiment R⁴ is H; CG-C₁-C₁₀ alkyl or aryl, whereineach alkyl or aryl is substituted with one or more R¹⁰ independently.

[0142] In another embodiment R⁴ is H; C₁-C₁₀ alkyl or aryl.

[0143] In another embodiment R⁴ is H, methyl or phenyl.

[0144] In another embodiment R⁵ is H; C₁-C₁₀ alkyl; aryl-C₁-C₅ alkylene;—C₁-C₅-alkyl-C(═O)-aryl; or heteroaryl-C₁-C₅ alkylene, wherein eachalkyl, aryl-C₁-C₅ alkylene and heteroaryl-C₁-C₅alkylene is optionallysubstituted with one or more R⁷ independently.

[0145] In another embodiment R⁵ is H; C₁-C₁₀ alkyl optionallysubstituted with one or more R⁷ independently; —C₁-C₅-alkyl-C(═O)-aryloptionally substituted with one or more R⁷ independently or C₂-C₁₀alkenyl optionally substituted with one or more R⁷ independently.

[0146] In another embodiment R⁵ is H, —C₁-C₅-alkyl-C(═O)-aryl optionallysubstituted with one or more R⁷ independently or C₁-C₁₀ alkyl optionallysubstituted with one or more R⁷ independently.

[0147] In another embodiment R⁵ is H or —C₁-C₅-alkyl-C(═O)-phenyloptionally substituted with one or more R⁷ independently.

[0148] In another embodiment R⁵ is methyl or ethyl optionallysubstituted with one or more R⁷ independently.

[0149] In another embodiment R⁵ is H; C₁-C₁₀ alkyl; aryl-C₁-C₅ alkylene;or heteroaryl-C₁-C₅ alkylene, wherein each alkyl, aryl-C₁-C₅ alkyleneand heteroaryl-C₁-C₅ alkylene is optionally substituted with one or moreR⁷ independently.

[0150] In another embodiment R⁵ is H; C₁-C₁₀ alkyl optionallysubstituted with one or more R⁷ independently; or C₂-C₁₀ alkenyloptionally substituted with one or more R⁷ independently.

[0151] In another embodiment R⁵ is H or C₁-C₁₀ alkyl optionallysubstituted with one or more R⁷ independently.

[0152] In another embodiment R⁵ is H

[0153] In another embodiment R⁵ is methyl

[0154] In another embodiment R⁵ is C₁-C₁₀ alkyl; aryl-C₁-C₅ alkylene; orheteroaryl-C₁-C₅ alkylene, wherein each alkyl, aryl-C₁-C₅ alkylene andheteroaryl-C₁-C₅ alkylene is optionally substituted with one or more R¹⁰independently.

[0155] In another embodiment R⁶ is C₁-C₁₀ alkyl; aryl-C₁-C₅ alkylene; orheteroaryl-C₁-C₅ alkylene.

[0156] In another embodiment R⁶ is C₁-C₁₀ alkyl optionally substitutedwith one or more R¹⁰ independently.

[0157] In another embodiment R⁵ is C₁-C₁₀ alkyl.

[0158] In another embodiment R⁶ is methyl or ethyl optionallysubstituted by one or more R¹⁰ independently.

[0159] In another embodiment R⁶ is methyl

[0160] In another embodiment R⁷ is H; ═O; C₁-C₁₀ alkyl; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; heteroaryl, OR¹⁰; N(R¹⁰)₂;SR¹⁰, cyano; or halogen, wherein each alkyl, cycloalkyl,cycloheteroalkyl, aryl, and heteroaryl is optionally substituted withone or more R¹⁰ independently.

[0161] In another embodiment R⁷ is ═O; OR¹⁰; C₃-C₇ cycloalkyl; C₃-C₇cycloheteroalkyl; aryl; heteroaryl; cyano; or halogen, wherein eachcycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is optionallysubstituted with one or more R¹⁰ independently.

[0162] In another embodiment R⁷ is ═O; OR¹⁰; cyano; halogen; C₃-C₇cycloalkyl optionally substituted with one or more R¹⁰ independently oraryl optionally substituted with one or more R¹⁰ independently.

[0163] In another embodiment R⁷ is H; ═O; C₁-C₁₀ alkyl; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; heteroaryl, OR¹⁰; N(R¹⁰)₂;SR¹⁰, wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl, andheteroaryl is optionally substituted with one or more R¹⁰ independently.

[0164] In another embodiment R⁷ is ═O; C₃-C₇ cycloalkyl; C₃-C₇cycloheteroalkyl; aryl; or heteroaryl, wherein each cycloalkyl,cycloheteroalkyl, aryl, and heteroaryl is optionally substituted withone or more R¹⁰ independently.

[0165] In another embodiment R⁷ is ═O; C₃-C₇ cycloalkyl optionallysubstituted with one or more R¹⁰ independently or aryl optionallysubstituted with one or more R¹⁰ independently

[0166] In another embodiment R⁷ is ═O or aryl optionally substitutedwith one or more R¹⁰ independently.

[0167] In another embodiment R⁷ is ═O or phenyl optionally substitutedby one or more R¹⁰ independently.

[0168] In another embodiment R⁸ is aryl or heteroaryl, wherein each aryland heteroaryl is optionally substituted with one or more R¹⁰independently.

[0169] In another embodiment R⁸ is aryl or heteroaryl.

[0170] In another embodiment R⁸ is phenyl.

[0171] In another embodiment R⁹ is H; C₁-C₁₀ alkyl; or halogen.

[0172] In another embodiment R⁹ is H.

[0173] In another embodiment R¹⁰ is H; —CF₃; —OH; cyano; halogen; —OCF₃;or —OCH₃.

[0174] In another embodiment R¹⁰ is H; cyano; halogen; or —OCH₃.

[0175] In another embodiment R¹¹ is H.

[0176] In another embodiment R¹² is H.

[0177] Compounds of either formula I or formula 11 may be used for themanufacture of a medicament for treating diseases associated withproteins that are subject to inactivation by DPP-IV.

[0178] A further aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for treating a conditionthat may be regulated or normalised via inhibition of DPP-IV.

[0179] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for treatment of metabolicdisorders.

[0180] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for blood glucoselowering.

[0181] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for treatment of Type 2diabetes

[0182] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for the treatment ofimpaired glucose tolerance (IGT).

[0183] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for the treatment ofimpaired fasting glucose (IFG).

[0184] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for prevention ofhyperglycemia.

[0185] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for delaying theprogression of impaired glucose tolerance (IGT) to Type 2 diabetes.

[0186] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for delaying theprogression of non-insulin requiring Type 2 diabetes toinsulin-requiring Type 2 diabetes.

[0187] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for increasing the numberand/or the size of beta cells in a mammalian subject.

[0188] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for treatment of beta celldegeneration, in particular apoptosis of beta cells.

[0189] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for the treatment ofdisorders of food intake.

[0190] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for the treatment ofobesity.

[0191] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for appetite regulation orinduction of satiety.

[0192] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for the treatment ofdyslipidemia.

[0193] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for treatment offunctional dyspepsia, in particular irritable bowel syndrome.

[0194] A further aspect of the invention is a method for treating anyone of the conditions mentioned above by administering to a subject inneed thereof an effective amount of a compound of the invention.

[0195] A further aspect of the invention is a pharmaceutical compositionsuitable for treating any one of the conditions mentioned abovecomprising a compound of the invention.

[0196] The compounds of the present invention may be prepared in theform of pharmaceutically acceptable salts, especially acid-additionsalts, including salts of organic acids and mineral acids. Examples ofsuch salts include salts of organic acids such as formic acid, fumaricacid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvicacid, oxalic acid, succinic acid, malic acid, tartaric acid, citricacid, benzoic acid, salicylic acid and the like. Suitable inorganicacid-addition salts include salts of hydrochloric, hydrobromic,sulphuric and phosphoric acids and the like. Further examples ofpharmaceutically acceptable inorganic or organic acid addition saltsinclude the pharmaceutically acceptable salts listed in Journal ofPharmaceutical Science, 66, 2 (1977) that are known to the skilledartisan.

[0197] Also intended as pharmaceutically acceptable acid addition saltsare the hydrates that the present compounds are able to form.

[0198] The acid addition salts may be obtained as the direct products ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid, and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent.

[0199] The compounds of this invention may form solvates with standardlow molecular weight solvents using methods known to the skilledartisan.

[0200] It is to be understood that the invention extends to all of thestereo isomeric forms of the claimed compounds, as well as theracemates.

[0201] Pharmaceutical Compositions

[0202] In another aspect, the present invention includes within itsscope pharmaceutical compositions comprising, as an active ingredient,at least one compound of the invention which inhibits the enzymaticactivity of DPP-IV or a pharmaceutically acceptable salt or prodrug orhydrate thereof together with a pharmaceutically acceptable carrier ordiluent.

[0203] Pharmaceutical compositions containing a compound of theinvention of the present invention may be prepared by conventionaltechniques, e.g. as described in Remington: The Science and Practice ofPharmacy, 19th Ed., 1995. The compositions may appear in conventionalforms, for example capsules, tablets, aerosols, solutions, suspensionsor topical applications.

[0204] Typical compositions include a compound of the invention whichinhibits the enzymatic activity of DPP-IV or a pharmaceuticallyacceptable basic addition salt or prodrug or hydrate thereof, associatedwith a pharmaceutically acceptable excipient which may be a carrier or adiluent or be diluted by a carrier, or enclosed within a carrier whichcan be in the form of a capsule, sachet, paper or other container. Inmaking the compositions, conventional techniques for the preparation ofpharmaceutical compositions may be used. For example, the activecompound will usually be mixed with a carrier, or diluted by a carrier,or enclosed within a carrier which may be in the form of an ampoule,capsule, sachet, paper, or other container. When the carrier serves as adiluent, it may be solid, semi-solid, or liquid material which acts as avehicle, excipient, or medium for the active compound. The activecompound can be adsorbed on a granular solid container for example in asachet. Some examples of suitable carriers are water, salt solutions,alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil,peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, dextrin,magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate,talc, gelatine, agar, pectin, acacia, stearic acid or lower alkyl ethersof cellulose, silicic acid, fatty acids, fatty acid amines, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.Similarly, the carrier or diluent may include any sustained releasematerial known in the art, such as glyceryl monostearate or glyceryldistearate, alone or mixed with a wax. The formulations may also includewelting agents, emulsifying and suspending agents, preserving agents,sweetening agents or flavouring agents. The formulations of theinvention may be formulated so as to provide quick, sustained, ordelayed release of the active ingredient after administration to thepatient by employing procedures well known in the art.

[0205] The pharmaceutical compositions can be sterilized and mixed, ifdesired, with auxiliary agents, emulsifiers, salt for influencingosmotic pressure, buffers and/or colouring substances and the like,which do not deleteriously react with the active compounds. The route ofadministration may be any route, which effectively transports the activecompound of the invention which inhibits the enzymatic activity ofDPP-IV to the appropriate or desired site of action, such as oral,nasal, pulmonary, buccal, subdermal, intradermal, transdermal orparenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral,intramuscular, intranasal, ophthalmic solution or an ointment, the oralroute being preferred.

[0206] If a solid carrier is used for oral administration, thepreparation may be tabletted, placed in a hard gelatin capsule in powderor pellet form or it can be in the form of a troche or lozenge. If aliquid carrier is used, the preparation may be in the form of a syrup,emulsion, soft gelatin capsule or sterile injectable liquid such as anaqueous or non-aqueous liquid suspension or solution.

[0207] For nasal administration, the preparation may contain a compoundof the invention which inhibits the enzymatic activity of DPP-IV,dissolved or suspended in a liquid carrier, in particular an aqueouscarrier, for aerosol application. The carrier may contain additives suchas solubilizing agents, e.g. propylene glycol, surfactants, absorptionenhancers such as lecithin (phosphatidylcholine) or cyclodextrin, orpreservatives such as parabenes.

[0208] For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil. Tablets, dragees, orcapsules having talc and/or a carbohydrate carrier or binder or the likeare particularly suitable for oral application. Preferable carriers fortablets, dragees, or capsules include lactose, corn starch, and/orpotato starch. A syrup or elixir can be used in cases where a sweetenedvehicle can be employed.

[0209] A typical tablet which may be prepared by conventional tablettingtechniques may contain: Core: Active compound (as free compound or saltthereof) 250 mg Colloidal silicon dioxide (Aerosil) ® 1.5 mg Cellulose,microcryst. (Avicel) ® 70 mg Modified cellulose gum (Ac-Di-Sol) ® 7.5 mgMagnesium stearate Ad. Coating: HPMC approx. 9 mg *Mywacett 9-40 Tapprox. 0.9 mg

[0210] The compounds of the invention are effective over a wide dosagerange. For example, in the treatment of adult humans, dosages from about0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, perday may be used. A most preferable dosage is about 0.5 mg to about 250mg per day. In choosing a regimen for patients it may frequently benecessary to begin with a higher dosage and when the condition is undercontrol to reduce the dosage. The exact dosage will depend upon the modeof administration, on the therapy desired, form in which administered,the subject to be treated and the body weight of the subject to betreated, and the preference and experience of the physician orveterinarian in charge.

[0211] Generally, the compounds of the present invention are dispensedin unit dosage form comprising from about 0.05 to about 1000 mg ofactive ingredient together with a pharmaceutically acceptable carrierper unit dosage.

[0212] Usually, dosage forms suitable for oral, nasal, pulmonal ortransdermal administration comprise from about 0.05 mg to about 1000 mg,preferably from about 0.5 mg to about 250 mg of the compounds admixedwith a pharmaceutically acceptable carrier or diluent.

[0213] The invention also encompasses prodrugs of a compound of theinvention which on administration undergo chemical conversion bymetabolic processes before becoming active pharmacological substances.In general, such prodrugs will be functional derivatives of a compoundof the invention which are readily convertible in vivo into a compoundof the invention. Conventional procedures for the selection andpreparation of suitable prodrug derivatives are described, for example,in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

[0214] Combination Treatments

[0215] The invention furthermore relates to the use of a compoundaccording to the present invention for the preparation of a medicamentfor use in the treatment of diabetes in a regimen which additionallycomprises treatment with another antidiabetic agent.

[0216] In the present context the expression “antidiabetic agent”includes compounds for the treatment and/or prophylaxis of insulinresistance and diseases wherein insulin resistance is thepathophysiological mechanism.

[0217] In one embodiment of this invention, the antidiabetic agent isinsulin or GLP-1 or any analogue or derivative thereof.

[0218] In another embodiment the antidiabetic agent is a hypoglycemicagent, preferably an oral hypoglycemic agent.

[0219] Oral hypoglycemic agents are preferably selected from the groupconsisting of sulfonylureas, non-sulphonylurea insulin secretagogues,biguamides, thiazolidinediones, alpha glucosidase inhibitors, glucagonantagonists, GLP-1 agonists, potassium channel openers, insulinsensitizers, hepatic enzyme inhibitors, glucose uptake modulators,compounds modifying the lipid metabolism, compounds lowering foodintake, and agents acting on the ATP-dependent potassium channel of theβ-cells.

[0220] Among the sulfonylureas, tolbutamide, glibenclamide, glipizideand gliclazide are preferred.

[0221] Among the non-sulphonylurea insulin secretagogues, repaglinideand nateglinide are preferred.

[0222] Among the biguamides, mefformin is preferred.

[0223] Among the thiazolidinediones, troglitazone, rosiglitazone andciglitazone are preferred.

[0224] Among the glucosidase inhibitors, acarbose is preferred.

[0225] Among the agents acting on the ATP-dependent potassium channel ofthe β-cells the following are preferred: glibenclamide, glipizide,gliclazide, repaglinide.

[0226] The cyclic amines used in the synthesis of the compounds of theinvention are either commercially available, or have been made usingpublished procedures. Racemic 3-aminopiperidine was made from3-aminopyridine by reduction with PtO₂ (Nienburg. Chem. Ber.70(1937)635). Enantiopure (R)— and (S)-3-aminopiperidine and (R)— and(S)-3-Aminopyrrolidine was made according to Moon, S—H and Lee, S.Synth. Commun. 28(1998)3919.

[0227] Pharmacological Methods

[0228] Methods for Measuring the Activity of Compounds which Inhibit theEnzymatic Activity of CD26/DPP-IV

SUMMARY

[0229] Chemical compounds are tested for their ability to inhibit theenzyme activity of purified CD26/DPP-IV. Briefly, the activity ofCD26/DPP-IV is measured in vitro by its ability to cleave the syntheticsubstrate Gly-Pro-p-nitroanilide (Gly-Pro-pNA). Cleavage of Gly-Pro-pNAby DPP-IV liberates the product p-nitroanilide (pNA), whose rate ofappearance is directly proportional to the enzyme activity. Inhibitionof the enzyme activity by specific enzyme inhibitors slows down thegeneration of pNA. Stronger interaction between an inhibitor and theenzyme results in a slower rate of generation of pNA. Thus, the degreeof inhibition of the rate of α-cumulation of pNA is a direct measure ofthe strength of enzyme inhibition. The accumulation of pNA is measuredspectrophotometrically. The inhibition constant, Ki, for each compoundis determined by incubating fixed amounts of enzyme with severaldifferent concentrations of inhibitor and substrate.

[0230] Materials:

[0231] The following reagents and cells are commercially available:

[0232] Porcine CD26/DPP-IV (Sigma D-7052), Gly-Pro-pNA (Sigma G0513).

[0233] Assay buffer: 50 mM Tris pH 7.4, 150 mM NaCl, 0.1% Triton X-100.

[0234] Gly-Pro-pNA Cleavage-Assay for CD26:

[0235] The activity of purified CD26/DPP-IV is assayed in reactionscontaining:

[0236] 70 μl assay buffer

[0237] 10 μl inhibitor or buffer

[0238] 10 μl substrate (Gly-Pro-pNA from a 0.1 M stock solution inwater) or buffer

[0239] 10 μl enzyme or buffer

[0240] Reactions containing identical amounts of enzyme, but varyingconcentrations of inhibitor and substrate, or buffer as control, are setup in parallel in individual wells of a 96-well ELISA plate. The plateis incubated at 25° C. and absorbance is read at 405 nm after 60 minincubation. The inhibitor constants are calculated by non-linearregression hyperbolic fit and the result is expressed as inhibitionconstant (Ki) in nM.

[0241] Diabetes Model

[0242] The Zucker Diabetic Fatty (ZDF) rat model can be used toinvestigate the effects of the compounds of the invention on both thetreatment and prevention of diabetes as rats of this sub-strain areinitially pre-diabetic although develop severe type 2 diabetescharacterised by increased HbA1c levels over a period of 6 weeks. Thesame strain can be used to predict the clinical efficacy of otheranti-diabetic drug types. For example, the model predicts the potencyand limited clinical efficacy of thiazolidinedione insulin sensitizerscompounds.

[0243] Chemical Methods

[0244] Preparative HPLC (Method A1)

[0245] Column: 1.9×15 cm Waters XTerra RP-18. Buffer: linear gradient5-95% in 15 min, MeCN, 0.1% TFA, flow rate of 15 ml/min. The pooledfractions are either evaporated to dryness in vacuo, or evaporated invacuo until the MeCN is removed, and then frozen and freeze dried.

[0246] Preparative HPLC (Method A2)

[0247] Column: Supelcosil ABZ+Plus, 25 cm×10 mm, 5 μm. Solvent A: 0.1%TFA/Water, solvent B: MeCN. Eluent composition: 5 min. 100% A, lineargradient 0-100% B in 7 min, 100% B in 2 min. Flow rate 5 ml/min. Thecolumn is allowed to equilibrate for 4 min in 100% A before the nextrun.

[0248] Preparative HPLC (Method A3)

[0249] The LC system consists of a Gilson 321 pump, 235 injector and215-fraction collector equipped with a Waters Xterra 7.8 mm*100 mmcolumn run with a gradient from 10% aqueous acetonitrile with 0.01% TFAto 100% acetonitrile with 0.01% TFA over 11 min. Flow rate 10 ml/min.The effluent is split 1:1000 to an Agilent 1100 MSD by a LC Packings ACM10-50 flow splitter. The MS is equipped with an Agilent fractioncollector kit, from which the analogue signal from extracted the targetion, is used for controlling fraction collection.

[0250] HPLC-MS (Method B1)

[0251] Column: Waters Xterra MS C-18×3 mm id. Buffer: Linear gradient10-100% in 7.5 min, MeCN, 0.01% TFA, flow rate 1.0 ml/min. Detection 210nm (analog output from diode array detector), MS-detection ionisationmode API-ES, scan 100-1000 amu step 0.1 amu.

[0252] HPLC-MS (Method B2)

[0253] Column: 0.3 mm×15 cm Waters Symmetry C₁₈. Buffer: Linear gradient5-90% in 15 min, MeCN, 0.05% TFA, flow rate 1 ml/min

[0254] Analytical Separation of Stereoisomers (Method C)

[0255] CCE. Chiral capillary electrophoresis: Conditions: HP 3DCapillary Electrophoresis: 48.5/40 cm, 50 μm HP bubble capillary,Electrolyte: HS-p-CD (Regis) (2% w/v) in 50 mM phosphate buffer pH 2.5(HP), Voltage: −17 kV, Injection: 30 mbar for 5 s.

[0256] Preparative Separation of Stereoisomers (Method D)

[0257] Analytical separations were performed on Hewlett Packard 1090HPLC equipment with 5 chiral Daicel columns (AD, OD, AS, OJ andWelko-02, 250×4.6 mm) with a diode array detector. The mobile phaseswere 2-propanol:heptane mixtures with 0.1% DEA.

[0258] Preparative separations were performed with the above-mentionedtype of columns (250×20 mm) on a preparative Gilson HPLC set-up.Relevant fractions were collected and evaporated (SpeedVac).

[0259] Microwave Assisted Reactions (Method F)

[0260] The reactants are mixed in an appropriate solvent in a closedTeflon vessel (XP 1500 Plus Vessel set) and heated in a micro wave oven(CEM MARSX microwave instrument. Magnetron frequency: 2455 MHz. PowerOutput: 1200 Waft.). The reaction mixture is cooled and evaporated invacuo. Normally solvents like MeOH; EtOH, iPrOH; H₂O; DMF and DMSO areused. Abbreviations DCHMA Dicyclohexylmethylamine DCM DichloromethaneDEA Diethylamine DIEA Diisopropylethylamine DMF Dimethylformamide DMSODimethyl sulfoxide EtOAc Ethyl acetate HOAc Acetic acid MeCNAcetonitrile TFA Trifluoroacetic acid THF Tetrahydrofuran TMGTetramethylguanidine

[0261] Preparation of Cis-Cycloheptane-1,2-Diamine:

[0262] Step A: 2-Bromo-Cycloheptanone

[0263] Cycloheptanon (26 ml, 0.22 mmol) was dissolved in acetic acid (25ml) and water (35 ml) and heated to 50° C. Bromine (11, 1 ml, 0.22 mmol)was added drop wise, and the reaction was cooled to room temperature.Potassium carbonate (50 g) was added in small portions, and the solutionwas poured into water (200 ml). The aqueous layer was extracted withdichloromethane (1×400 ml and 2×200 ml). The combined organics werewashed with water (150 ml), dried over sodium sulphate, filtered andevaporated to afford 2-bromocycloheptanone.

[0264] Yield: 21.4 g, (50%).

[0265]¹H-NMR (CDCl₃, 200 MHz) δ=4.4(1H, q); 3,75 (1H, m), 2.5-1.3 (10H,m).

[0266] Step B: 3,4,5,6,7,8-Hexahydro-1H-cycloheptaimidazol-2-one

[0267] Urea (6,54 g, 108.86 mmol) and diethyleneglycol diethylether (10ml) were heated to reflux and 2-bromo-cycloheptanone (10.4 g, 54.43mmol) was added drop wise. The mixture was stirred 2 hours at 140° C.,and then cooled to room temperature. Water (20 ml) was added and theprecipitate was collected by filtration. The crystals wererecrystallized from boiling ethanol to afford3,4,5,6,7,8-hexahydro-1H-cycloheptaimidazol-2-one.

[0268] Yield: 1.64 g, (20%).

[0269] HPLC-MS (Method B1): m/z=153 (M+1); R_(t)=1.843 min.

[0270] Step C: Cis-Octahydro-cycloheptaimidazol-2-one3,4,5,6,7,8-Hexahydro-1H-cycloheptaimidazol-2-one (1,62 g, 10.64 mmol)was suspended in ethanol (60 ml) and Raney Nickel was added under anitrogen atmosphere. The mixture was stirred in a hydrogen atmosphere at135° C. and 55 bar for 20 hours. The reaction mixture was filtered andwashed with ethanol, and the filtrate was evaporated to affordcis-otahydrocycloheptaimidazol-2-one as crystals.

[0271] Yield: 1.3 g, (79%).

[0272] HPLC-MS (Method B1): m/z=155 (M+1); R_(t)=1.77 min.

[0273] Step D: Cis-Cycloheptane-1,2-diamine

[0274] cis-Otahydro-cycloheptaimidazol-2-one (1.30 g, 8.43 mmol) wasdissolved in 65% sulphuric acid (15,8 ml) and heated to 145° C. for 2days. The reaction mixture was cooled to room temperature and water (40ml) was added. The mixture was added 50% sodium hydroxide until pH=10.The organic material was extracted into diethyl ether (4×350 ml), andthe combined organic layers were dried with sodium sulphate, filteredand evaporated to afford the title compound.

[0275] Yield: 950 mg (88%).

[0276] HPLC-MS (Method B1): m/z=129 (M+1); R_(t)=0.53 min.

[0277] Preparation of 8-bromo-3-methyl-3,7-dihydropurine-2,6-dione

[0278] Step A:N-(6-Amino-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)formamide

[0279] Formic acid (400 ml) was cooled to 4° C. and6-amino-1-methyluracil (50 g, 355 mol) was added. Sodium nitrite (24.42g, 354 mol) was added in small portions over 10 minutes, and the mixturewas stirred 3 hours at 10° C. The mixture was heated to 35° C. andplatin on carbon (708 mg), water (18.7 ml), and formic acid (75 ml) wereadded. The reaction was stirred for 2 days and then filtered, and thesolvents were evaporated. The crude product was crystallised fromacetone to affordN-(6-amino-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)formamide.

[0280] Yield: 68.4 g (99%).

[0281] HPLC-MS (Method B2): m/z=185 (M+1); R_(t)=0.506 min.

[0282] Step B: 3-Methyl-3,7-dihydropurine-2,6-dione

[0283]N-(6-amino-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)formamide(68.4 g, 371 mol) and 2.5M sodium hydroxide (400 ml) were heated to 80°C. for 2 hours. The mixture was allowed to cool to room temperature and6M hydrochloric acid (180 ml) was added (pH=2). The precipitate wascollected by filtration to afford 3-methyl-3,7-dihydropurine-2,6-dione.

[0284] Yield: 36.7 g (60%).

[0285] HPLC-MS (Method B2): m/z=167 (M+1); R_(t)=0.571 min.

[0286] Step C: 8-Bromo-3-methyl-3,7-dihydro-purine-2,6-dione

[0287] 3-Methyl-3,7-dihydropurine-2,6-dione (36.7 g, 221 mmol) andacetic acid (700 ml) were refluxed, and sodium acetate (39.1 g, 288mmol) was added. The mixture was allowed to cool to 65° C., and bromine(23 ml, 448 mmol) dissolved in acetic acid (100 ml) was added drop wiseover 30 minutes. The reaction was stirred for 3 days, and then filtered.The isolated crystals were washed with acetic acid (2×50 ml), water(2×100 ml), and acetic acid (1×50 ml) to afford the title compound.

[0288] Yield: 41.3 g, (79%).

[0289] HPLC-MS (Method B2): m/z=245 (M+); R_(t)=0.918 min.

[0290] General Procedure (A):

[0291] Step A:

[0292] The starting material (16 μmol) is dissolved in a mixture of DMFand DIEA (3% DIEA, 250 μl). The alkylation reagent R¹—CR⁹R⁹—X (16.8μmol, 1.05 equiv) is dissolved in DMF (100 μl) and added. The mixture isheated to 65° C. for 2 h.

[0293] Step B:

[0294] Alkylation reagent R⁵—Br (32 μmol) is dissolved in DMF (100 μl)and added to the reaction mixture followed by a solution of TMG in DMF(1.16 ml TMG diluted to 5.8 ml, 48 μl). The mixture is kept at 65° C.for 4 h. Volatiles are stripped

[0295] Step C:

[0296] The diamine (200 μmol) is dissolved in a mixture of DMSO andDCHMA (3% DCHMA, 200 μl) and added to the reaction mixture. The reactionis kept at 50° C. for 44 h.

[0297] Samples are neutralized using HOAc (20 pi), stripped and purifiedby HPLC (Method A2).

[0298] General Procedure (B):

[0299] Step A:

[0300] The starting material (32 μmol) is dissolved in a mixture of DMFand DIEA (3% DIEA, 500 μl). The alkylation reagent R¹—CR⁹R⁹—X (33.6μmol, 1.05 equiv) is dissolved in DMF (200 μl) and added. The mixture isheated to 65° C. for 2 h. Upon cooling to 25° C., K₂CO₃ (aq) is added(5.12M, 50 μL, 256 mmol). Volatiles are stripped.

[0301] Step B:

[0302] Alkylation reagent R⁵—Br (64 μmol) is dissolved in DMF (250 μl)and added to the reaction mixture. The mixture is kept at 25° C. for 48h. Volatiles are stripped

[0303] Step C:

[0304] The diamine (400 μmol) is dissolved in DMSO and added to thereaction mixture. If the dihydrochloride salt of the diamine isemployed, four equivalents of DCHMA are added. The reaction is kept at50° C. for 48 h. Samples are neutralized using HOAc (30 μl), andpurified by HPLC (Method A3).

[0305] General Procedure (C)

[0306] Step A:

[0307] The starting material (4.08 mmol) is dissolved in a mixture ofDMF and DIEA (3% DIEA, 65 ml). The alkylation reagent R¹—CR⁹R⁹—X (4.28mmol, 1.05 equiv) is dissolved in DMF (25.5 ml) and added. The mixtureis heated to 65° C. for 2 h and poured onto ice followed by filtrationof the alkylated product.

[0308] Step B:

[0309] Diamine (400 μmol) is dissolved in DMSO (400 μl) and added to theabove product (32 mmol). The reaction is kept at 50° C. for 24-48 h.Samples are neutralized using HOAc (30 μl) and purified by HPLC (MethodA2) or (Method A1)

[0310] General Procedure (D)

[0311] Step A:

[0312] The starting material (32 μmol) is dissolved in a mixture of DMFand DIEA (3% DIEA, 500 μl). The alkylation reagent R¹—CR⁹R⁹—X (33.6μmol, 1.05 equiv) is dissolved in DMF (200 μl) and added. The mixture isheated to 65° C. for 2 h.

[0313] Step B:

[0314] Diamine (400 μmol) is dissolved in DMSO (400 μl) and added to theabove reaction mixture. The reaction is kept at 50° C. for 48 h.

[0315] Samples are neutralized using HOAc (30 μl) and purified by HPLC(Method A2).

[0316] General Procedure (E):

[0317] Step A:

[0318] The starting material (20.40 mmol) is dissolved in DMF (50 ml)and DIEA (10 mL). The alkylation reagent R¹—CR⁹R⁹—X (22.03 mmol, 1.08equiv) is dissolved in DMF (10 ml) and added. Heating the mixture to 65°C. for 2 h affords the products that are isolated by filtration uponadding the reaction mixture onto ice (300 mL).

[0319] Step B:

[0320] The product from Step A (5.56 mmol) and alkylation reagent R⁵—Br(11.11 mmol) are dissolved in DMF (60 mL) and potassium carbonate isadded to the reaction mixture. Upon stirring at 25° C. for 16 h thereaction mixture is poured onto ice (300 ml) and the product is isolatedby filtration and dried in vacuo.

[0321] Step C:

[0322] The product from Step B (0.472 mmol) is dissolved in DMSO (5 ml)and the diamine (2.36 mmol) is added to the reaction mixture. If thedihydrochloride salt of the diamine is employed, K₂CO₃ (2.36 mmol) isadded. The reaction is kept at 50° C. for 24 h and poured onto ice (20ml). The product is isolated by filtration.

EXAMPLES Example 1 General Procedure (A)

[0323] (±)Cis-8-(2-Aminocyclohexylamino)-7-benzyl-3-methyl-1-(2-oxo-2-phenylethyl)-3,7-dihydropurine-2,6-dione

[0324]¹H NMR (DMSO-d₆): δ 8.10-8.01 (m, 2H); 7.82 (s br, 3H); 7.71 (t,1H); 7.57 (t, 2H); 7.38-7.17 (m, 5H); 6.73 (d, 1H); 5.51-5.23 (m, 4H);4.29-4.17 (m, 1H); 3.59 (s br, 1H); 3.42 (s, 3H); 1.89-1.29 (m, 8H).HPLC-MS (Method B1): m/z=487 (M+1); R_(t)=3.087 min

Example 2 General Procedure (A)

[0325] (±)Cis-8-(2-Aminocyclohexylamino)-7-(2-chlorobenzyl)-1-(2-hydroxy-2-phenylethyl)-3-methyl-3,7-dihydropurine-2,6-dione

[0326] Styrene oxide was employed instead of R⁵—X

[0327]¹H NMR (DMSO-d₆): δ 7.79 (s br, 3H); 7.55-7,48 (m, 1H); 7,38-7,15(m, 7H); 6,81-6,71 (m, 1H); 6,63-6,54 (m, 1H); 5.59-5.35 (m, 2H);4.93-4.81 (m, 1H); 4.24 (s br, 1H); 4.14-4.04 (m, 1H); 3.41 (s, 3H);1.86-1.29 (m, 8H). HPLC-MS (Method B1): m/z=523 (M+1); R_(t)=3.058 min.

Example 3 General Procedure (C)

[0328]8-(2-(S)-Aminocyclohexyl-(S)-amino)-7-(2-iodobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione

[0329]¹H NMR (DMSO-d₆): δ 10.68 (s, 1H); 9.92 (d, 1H); 7.85 (s br, 3H);7.32 (t, 1H); 7.12-6.97 (m, 2H); 6.42 (d, 1H); 5.36-4.96 (dd, 2H);3.86-3.68 (m, 1H); 3.36 (s, 3H); 3.09-2.93 (m, 1H) 2.08-1.12 (m, 8H).HPLC-MS (Method B1): m/z=495 (M+1); R_(t)=2.313 min.

Example 4 General Procedure (C)

[0330]8-(2-(R)-Aminocyclohexyl-(R)-amino)-7-(2-iodobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione

[0331]¹H NMR (DMSO-d₆): δ 10.68 (s, 1H); 7.92 (d, 1H); 7.85 (s br, 3H);7.33 (t, 1H); 7.10-7.00 (m, 2H); 6.42 (m, 1H); 5.29 (d, 1H); 5.03 (d,1H); 3.77 (m, 1H); 3.36 (s, 3H); 3.01 (m, 1H); 1.98 (m, 2H); 1.69 (m,2H); 1.42 (m, 1H); 1.24 (m, 3H). HPLC-MS (Method B2): m/z=495 (M+1);R_(t)=3.70 min.

Example 5 General Procedure (C)

[0332] (±)Cis-8-(2-Aminocyclohexylamino)-7-(2-iodobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione

[0333]¹H NMR (DMSO-d₆): δ 10.67 (s, 1H); 7.91 (d, 1H); 7.76 (s br, 3H);7.31 (t, 1H); 7.04 (t, 1H); 6.73 (d, 1H); 6.44 (d, 1H); 5.39-5.14 (m,2H); 1.06 (s br, 1H); 3.59 (s br, 1H); 3.35 (s, 3H); 1.86-1-28 (m, 8H).HPLC-MS (Method B1): m/z=495 (M+1) R_(t)=2.313

Example 6 General Procedure (C)

[0334]8-(2-(S)-Aminocyclohexyl-(S)-amino)-7-biphenyl-2-ylmethyl-3-methyl-3,7-dihydropurine-2,6-dione

[0335]¹H NMR (DMSO-d₆): δ 10.58 (s, 1H); 7.87 (s br, 3H); 7.55-7.23 (m,7H); 7.03 (d, 1H); 6.58 (d, 1H); 5.37 (d, 1H); 5.11 (d, 1H); 3.78 (m,1H); 3.34 (s, 3H); 3.02 (m, 1H); 2.03 (m, 2H); 1.74 (m, 2H); 1.45 (m,1H); 1.26 (m, 3H). HPLC-MS (Method B2): m/z=445 (M+1); R_(t)=4.03 min.

Example 7 General Procedure (C)

[0336] (±)Cis-8-(2-Aminocyclohexylamino)-7-biphenyl-2-ylmethyl-3-methyl-3,7-dihydropurine-2,6-dione

[0337]¹H NMR (DMSO-d₆): δ 10.57 (s, 1H); 7.79 (s br, 3H); 7.50-7.22 (m,8H); 6.66 (d, 1H); 6.54 (d, 1H); 5.39 (d, 1H); 5.24 (d, 1H); 4.22 (m,1H); 3.55 (m, 1H); 3.32 (s, 3H); 1.80-1.30 (m, 8H). HPLC-MS (Method B2):m/z=445 (M+1); R_(t)=3.92.

Example 8 General Procedure (C)

[0338]8-(2-(S)-Aminocyclohexyl-(S)-amino)-7-(2-bromobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione

[0339]¹H NMR (DMSO-d₆): δ 10.68 (s, 1H); 7.87 (s br, 3H); 7.69 (d, 1H);7.37-7.19 (m, 2H); 7.045 (d, 1H); 6.51 (d, 1H); 5.46-5.08 (dd, 2H);3.87-3.71 (m, 1H); 3.36 (s, 3H); 3.10-2.92 (m, 1H); 2.09-1.09 (m, 8H).HPLC-MS (Method B1): m/z=449 (M+1); R_(t)=1.932 min.

Example 9 General procedure (C)

[0340] (±)Cis-8-(2-Aminocyclohexylamino)-7-(2-bromobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione

[0341]¹H NMR (DMSO-d₆): δ 10.67 (s, 1H); 7.77 (s br, 3H); 7.67 (d, 1H);7.36-7.17 (m, 2H); 6.74 (d, 1H); 5.51-5.26 (dd, 2H); 4.22 (s br, 1H);3.58 (s br, 1H); 3.35 (s, 3H); 1.87-1.28 (m, 8H).

[0342] HPLC-MS (Method B1): m/z=449 (M+1); R_(t)=1.926

Example 10 General Procedure (C)

[0343]8-(2-(S)-Aminocyclohexyl-(S)-amino)-7-(2-chlorobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione

[0344]¹H NMR (DMSO-d₆): δ 10.68 (s br, 1H); 7.86 (s br, 3H); 7.56-7.48(m, 1H); 7.37-7.22 (m, 2H); 7.10-6.99 (m, 1H); 6.61-6.52 (m, 1H)1.51-5.15 (dd, 2H); 3.86-3.69 (m. 1H); 3.36 (s, 3H); 3.08-2.93 (m, 1H);2.09-1.12 (m, 8H). HPLC-MS (Method B1): m/z=403 (M+1); R_(t) 2.184 min.

Example 11 General Procedure (C)

[0345]8-(2-(R)-Aminocyclohexyl-(R)-amino)-7-(2-chlorobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione

[0346]¹H NMR (DMSO-d₆): δ 10.68 (s, 1H); 7.92 (s br, 3H); 7.52 (d, 1H);7.30 (t+t, 2H); 7.08 (d, 1H); 6.57 (d, 1H); 5.44 (d, 1H); 5.21 (d, 1H);3.77 (m, 1H); 3.36 (s, 3H); 3.02 (m, 1H); 2.00 (m, 2H); 1.68 (m, 2H);1.42 (m, 1H); 1.23 (m, 3H).

Example 12 General Procedure (C)

[0347] (±)Cis-8-(2-Aminocyclohexylamino)-7-(2-chlorobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione

[0348]¹H NMR (DMSO-d₆): δ 10.68 (s br, 1H); 7.75 (s br, 3H); 7.505 (dd,1H); 7.35-7.22 (m, 2H); 7.76-6.58 (m, 2H); 5.52-5.33 (dd, 2H); 4.22 (sbr, 1H); 3.58 (s, 1H); 3.14 (s, 3H); 1.87-1.27 (m, 8H). HPLC-MS (MethodB1): m/z=403 (M+1); R_(t)=2.192 min.

Example 13 General Procedure (A)

[0349] (±)Cis-8-(2-Aminocyclohexylamino)-1,7-bis-(2-chlorobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione

[0350]¹H NMR (DMSO-d₆): δ 7.79 (s br, 3H); 7.50-7.37 (m, 2H); 7.35-7.10(m, 4H); 6.86 (d, 1H); 6.77 (d, 1H); 5.58 (d, 1H); 5.46 (dd, 2H); 4.99(s, 2H); 4.27 (m, 1H); 3.60 (m, 1H); 3.46 (s, 3H); 1.80-1.30 (m, 8H).(Method B2): m/z=527 (M+1); R_(t)=5.12 min.

Example 14 General Procedure (A)

[0351] (±)Cis-2-[8-(2-Aminocyclohexylamino)-7-(2-chlorobenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-1-ylmethyl]benzonitrile

[0352]¹H NMR (DMSO-d₆): δ 7.80 (s+d, 4H); 7.57 (t, 1H); 7.50 (d, 1H);7.41 (t, 1H); 7.29 (t+t, 2H); 7.09 (d, 1H); 6.86 (d, 1H); 6.68 (d, 1H);5.48 (dd, 2H); 5.12 (s, 2H); 4.26 (m, 1H); 3.60 (m, 1H); 3.44 (s, 3H);1.80-1.35 (m, 8H). (Method B2): m/z=518 (M+1); R_(t)=4.72 min.

Example 15 General Procedure (A)

[0353] (±)Cis-8-(2-Aminocyclohexylamino)-7-(2-chlorobenzyl)-3-methyl-1-(2-oxo-2-phenylethyl)-3,7-dihydropurine-2,6-dione

[0354]¹H NMR (DMSO-d₆): δ 8.01 (d, 2H); 7.77 (s br, 3H); 7.69 (t, 1H);7.55 (t, 2H); 7.49 (d, 1H); 7.29 m, 2H); 6.86 (d, 1H); 6.69 (d, 1H);5.46 (dd, 2H); 5.25 (dd, 2H): 4.28 (m, 1H); 3.64 (m, 1H); 3.46 (s, 3H);1.80-1.30 (m, 8H). (Method B2): m/z=521 (M+1); R_(t)=4.85 min.

Example 16 General Procedure (E)

[0355]8-(2-(R)-Aminocyclohexyl-(S)-amino)-7-(2-chlorobenzyl)-3-methyl-1-(2-oxo-2-phenylethyl)-3,7-dihydropurine-2,6-dione

[0356] The enantiomerically pure compound was isolated using (Method D).

[0357]¹H NMR (DMSO-d₆): δ 8.01 (d, J=7.54 Hz, 2H); 7.83 (s, 3H); 7.70(m, 1H); 7.53 (m, 3H); 7.30 (m, 2H); 6.92 (d, J=6.41 Hz, 1H); 6.67 (d,J=5.28 Hz, 1H); 5.51 (d, J=18.09 Hz, 1H); 5.43 (d, J=18.09 Hz, 1H); 5.29(d, J=18.00 Hz, 1H); 5.22 (d, J=18.00 Hz, 1H); 4.28 (s, 1H); 3.63 (s,1H); 3.46 (s, 3H); 1.67 (m, 6H); 1.40 (s, 2H).

Example 17 General Procedure (A)

[0358] (±)Cis-8-(2-Aminocyclohexylamino)-7-(2-chlorobenzyl)-3-methyl-1-phenethyl-3,7-dihydropurine-2,6-dione

[0359]¹H NMR (DMSO-d₆): δ 7.78 (s br, 3H); 1.52 (d, 1H); 7.35-7.24 (m,4H); 7.24-7.12 (m, 3H); 6.79 (d, 1H); 6.61 (d, 1H); 5.47 (dd, 2H); 4.24(m, 1H); 3.94 (t, 2H); 3.59 (m, 1H); 3.43 (s, 3H); 2.73 (t 1H);1.80-1.30 (m, 8H). (Method B2): m/z=507 (M+1); R_(t)=5.10 min.

Example 18 General Procedure (A)

[0360] (±)Cis-8-(2-Aminocyclohexylamino)-7-(2-bromobenzyl)-1-(2-chlorobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione

[0361]¹H NMR (DMSO-d₆): δ 7.76 (s br, 3H); 7.66 (d, 1H); 7.42 (d, 1H);7.40-7.15 (m, 4H); 6.87 (d, 1H); 6.77 (d, 1H); 6.62 (d, 1H); 5.41 (dd,2H); 4.98 (s, 2H); 4.27 (m, 1H); 3.61 (m, 1H); 3.46 (s, 3H); 1.80-1.35(m, 8H). (Method B2): m/z=573 (M+1); R_(t)=5.37 min

Example 19 General Procedure (A)

[0362] (±)Cis-2-[8-(2-Aminocyclohexylamino)-7-(2-bromobenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-1-ylmethyl]benzonitrile

[0363]¹H NMR (DMSO-d₆): W7.78 (d, 1H); 7.74 (s br, 3H); 7.67 (d, 1H);7.57 (t, 1H); 7.41 (t, 1H); 7.31 (t, 1H); 7.22 (t, 1H); 7.09 (d, 1H);6.86 (d, 1H); 6.61 (d, 1H); 5.42 (dd, 2H); 5.11 (s, 2H); 4.26 (m, 1H);3.61 (m, 1H); 3.45 (s, 3H); 1.80-1.35 (m, 8H). (Method B2): m/z=562(M+1); R_(t)=4.88

Example 20 General Procedure (A)

[0364] (±)Cis-8-(2-Aminocyclohexylamino)-7-(2-bromobenzyl)-3-methyl-1-(2-oxo-2-phenylethyl)-3,7-dihydropurine-2,6-dione

[0365]¹H NMR (DMSO-d₆): δ 8.01 (d, 2H); 7.74 (s br, 3H); 7.67 (m, 2H);7.55 (m, 2H); 7.32 (t, 1H); 7.25 (t, 1H); 6.88 (d, 1H); 6.61 (d, 1H);5.41 (dd, 2H); 5.25 (dd, 2H); 4.28 (m, 1H); 3.63 (m, 1H); 3.46 (s, 3H);1.80-1.35 (m, 8H). (Method B2): m/z=567 (M+1); R_(t)=5.02 min.

Example 21 General Procedure (A)

[0366] (±)Cis-8-(2-Aminocyclohexylamino)-7-(2-bromobenzyl)-3-methyl-1-phenethyl-3,7-dihydropurine-2,6-dione

[0367]¹H NMR (DMSO-d₆): δ 7.75 (s br, 3H); 7.69 (d, 1H); 7.35-7.10 (m,7H); 6.80 (d, 1H); 6.54 (d, 1H); 5.43 (dd, 2H); 4.23 (m, 1H); 3.94 (t,2H); 3.61 (m, 1H); 3.43 (s, 3H); 2.73 (2H); 1.80-1.30 (m, 8H). (MethodB2): m/z=551 (M+1); R_(t)=5.28 min.

Example 22 General Procedure (D)

[0368] (±)Cis-8-(2-Aminocyclohexylamino)-3-methyl-7-(2-methylbenzyl)-3,7-dihydropurine-2,6-dione

[0369] HPLC-MS (Method A3): m/z=383 (M+1); R_(t)=3.10 min.

Example 23 General Procedure (C)

[0370]8-(2-(S)-Aminocyclohexyl-(S)-amino)-1,3-dimethyl-7-(2-methylbenzyl)-3,7-dihydropurine-2,6-dione

[0371]¹H NMR (MeOH-d4): δ 7.16 (m, 4H), 6.47 (d 1H), 5.36 (dd, 2H), 3.98(m, 1H), 3.54 (s, 3H), 3.22 (s, 3H), 3.09 (m, 1H), 2.40 (s, 3H),1.20-2.34 (m, 10H)HPLC-MS (Method B1) m/z=397 (M+1); R_(t)=2.15 min

Example 24 General Procedure (D)

[0372] (±) C is8-(2-Aminocyclohexylamino)-1,3-dimethyl-7-(2-methylbenzyl)-3,7-dihydropurine-2,6-dione

[0373] HPLC-MS (Method A3): m/z=397 (M+1); R_(t)=3.50 min.

Example 25 General Procedure (D)

[0374] (±)Cis-8-(2-Aminocyclohexylamino)-7-(2-chlorobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione

[0375] HPLC-MS (Method A3): m/z=403 (M+1); R_(t)=3.10 min.

Example 26 General Procedure (D)

[0376] (±)Cis-8-(2-Aminocyclohexylamino)-7-(2,5-difluorobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione

[0377] HPLC-MS (Method A3): m/z=405 (M+1); R_(t)=3.30 min.

Example 27 General Procedure (C)

[0378] (±) Cis2-[8-(2-Aminocyclohexylamino)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl]benzonitrile

[0379]¹H NMR (MeOH-d4): δ 7.77(d, 1H), 7.60(t, 1H), 7.41 (t, 1H),7.06(d, 1H), 5.61(m, 3H), 4.37(s, 1H), 3.79(s, 1H), 3.50(m, 3H), 3.23(m,4H), 1.62(m, 9H). HPLC-MS (Method B1) m/z=408 (M+1); R_(t)=1.78 min.

Example 28 General Procedure (C)

[0380]2-[8-(2-(S)-Aminocyclohexyl-(S)-amino)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl]benzonitrile

[0381]¹H NMR (MeOH-d4): δ 7.53 (m, 4H), 7.00 (d, 1H), 5.58 (dd, 2H),3.99 (m, 1H), 3.52 (s, 3H), 3.21 (s, 3H), 3.12 (m, 1H), 1.20-2.22 (m,9H). HPLC-MS (Method B1) m/z=408 (M+1); R_(t) 1.84 min

Example 29

[0382] (±)Cis-2-[8-(2-Aminocycloheptylamino)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl]benzonitrile.TFA

[0383] Step A:2-(8-Bromo-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile(29A)

[0384] 8-Bromo-3-methyl-3,7-dihydropurine-2,6-dione (2,5 g, 10.2 mmol),dimethyl formamide (30 ml), 2-cyanobenzylbromid (2.15 g, 11.0 mmol), anddiisopropylethylamine (5 ml) were stirred at 65° C. for two days. Thesolvents were evaporated and the remaining was stirred with ethylacetate (150 ml) and water (150 ml) for 30 minutes. The precipitate wascollected by filtration to afford compound 29A as white crystals.

[0385] Yield: 3.20 g (87%).

[0386] HPLC-MS (Method B1): m/z=360 (M+), R_(t)=2,54 min.

[0387] Step B: (±)Cis-2-[8-(2-Aminocycloheptylamino)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl]benzonitrile.TFA (29)

[0388]2-(8-Bromo-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile(29A) (204 mg, 0.57 mmol) and potassium carbonate (391 mg, 2.83 mmol)were dissolved in DMSO (2 ml), and cis-cycloheptane-1,2-diamine (180 mg,1.4 mmol) was added. The mixture was stirred at 65° C. for four days,and then poured into water (20 ml) and dichloromethane (30 ml). Thelayers were separated and the aqueous layer was extracted withdichloromethane (2×30 ml). The combined organic layers were washed withwater, dried with sodium sulphate, filtered and evaporated. The crudeproduct was purified by preparative HPLC (method A1, Rt=7.27 min.) togive the title compound as a clear oil.

[0389] Yield: 53 mg (18%).

[0390]¹H NMR (300 MHz, DMSO-d₆): δ 1.3-1.9 (m, 10H); 3.3 (s, 3H); 3.5 (sbr, 1H); 4.4 (m, 1H); 5.5 (s, 2H); 6.7 (d, 1H); 6.8 (d, 1H); 7.5 (t,1H); 7.6 (t, 1H); 7.7 (s br, 3H), 7.9 (d, 1H); 10.7 (s, 1H). HPLC-MS(Method B1) m/z=408.3 (M+1); R_(t)=1.97 min.

Example 30

[0391] (±)Cis-8-(2-Aminocycloheptylamino)-7-(2-chlorobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione.TFA

[0392] Step A:8-Bromo-7-(2-chlorobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione (30A)

[0393] Compound 30A was prepared as described in the General procedureC, step A. HPLC-MS (Method B2) m/z=371 (M+2); R_(t)=3.031 min.

[0394] Step B: (±)Cis-8-(2-Aminocycloheptylamino)-7-(2-chlorobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione.TFA (30)

[0395] 8-Bromo-7-(2-chlorobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione(30A) (201 mg, 0.54 mmol) and cis-cycloheptane-1,2-diamine (139 mg, 1.1mmol) were reacted and purified as described in example 29, step B, toafford the title compound as white crystals.

[0396] Yield: 37 mg (16%).

[0397] Prep. HPLC (method A1): R_(t)=7.63 min.

[0398]¹H NMR (DMSO-d₆): δ 1.3-1.4 (m, 10H); 3.3 (s, 3H), 3.5 (s br, 1H);4.4 (m, 1H); 5.4 (2 d, 2H); 6.6 (dd, 1H); 6.7 (d, 1H); 7.3 (dq, 2H); 7.5(dd, 1H), 7.7 (s br, 3H), 10.7 (s, 1H). HPLC-MS (Method B1) m/z=417.1(M+1); R_(t)=2.34 min.

Example 31 General Procedure (C)

[0399]8-(2-(S)-Aminocyclohexyl-(S)-amino)-7-(2-chlorobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione

Example 32 General Procedure (D)

[0400] (±) Cis8-(2-Aminocyclohexylamino)-7-(2-chlorobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione

[0401] HPLC-MS (Method A3): m/z=417 (M+1); R_(t)=3.60 min.

Example 33 General Procedure (D)

[0402] (±)Cis-8-(2-Aminocyclohexylamino)-7-(2,3-difluorobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione

[0403] HPLC-MS (Method A3): m/z=419 (M+1); R_(t)=3.30 min.

Example 34

[0404] (±)Cis-2-[8-(2-Aminocycloheptylamino)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl]benzonitrile.TFA

[0405] Step A:2-(8-Chloro-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile(34A)

[0406] Compound 34A was prepared as described in the General procedureC, step A.

[0407] HPLC-MS (Method B1) m/z=330 (M+1); R_(t)=2.93 min.

[0408] Step B: (±)Cis-2-[8-(2-Aminocycloheptylamino)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl]benzonitrile.TFA (34)

[0409]2-(8-Chloro-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile(34A) (205 mg, 0.62 mmol) and cis-cycloheptane-1,2-diamine (159 mg, 1.2mmol) were reacted and purified as described in example 29, step B, toafford the title compound as white crystals.

[0410] Yield: 111 mg (42%).

[0411] Prep. HPLC (method A1): R_(t)=7.67 min.

[0412]¹H NMR (DMSO-d₆): δ 1.3-1.9 (m, 10H); 3.1 (s, 3H), 3.4 (s, 3H);3.5 (s br, 1H); 4.4 (m, 1H); 5.6 (s, 2H); 6.8 (dd, 2H); 7.5 (dd, 1H);7.6 (ddd, 1H); 7.5 (dd, 1H), 7.8 (s br, 3H), 7.9 (dd, 1H).

[0413] HPLC-MS (Method B1) m/z=422.2 (M+1); R_(t)=2.16 min.

Example 35

[0414] (±)Cis-8-(2-Aminocycloheptylamino)-7-(2-chlorobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.TFA

[0415] Step A:8-Chloro-7-(2-chlorobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione(35A)

[0416] Compound 35A was prepared as described in the General procedureC, step A.

[0417] HPLC-MS (Method B1) m/z=339 (M+); R_(t)=3.95 min.

[0418] Step B: (±)Cis-8-(2-Aminocycloheptylamino)-7-(2-chlorobenzyl)-1.3-dimethyl-3,7-dihydropurine-2,6-dione.TFA (35)

[0419]8-Chloro-7-(2-chlorobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione(35A) (200 mg, 0.59 mmol) and cis-cycloheptane-1,2-diamine (151 mg, 1.2mmol) were reacted and purified as described in example 29, step B, toafford the title compound as white crystals.

[0420] Yield: 31 mg (11%).

[0421] Prep. HPLC (method A1): R_(t)=8.25 min.

[0422]¹H NMR (DMSO-d₆): δ 1.3-1.9 (m, 10H); 3.1 (s, 3H), 3.4 (s, 3H);3.5 (s br, 1H); 4.4 (m, 1H); 5.4 (2 d, 2H); 6.6 (dd, 1H); 6.7 (d, 1H);7.3 (2 dd, 2H); 7.5 (d, 1H); 7.7 (s br, 3H). HPLC-MS (Method B1)m/z=431.2 (M+1); R_(t)=2.49 min.

Example 36 General Procedure (D)

[0423] (±)Cis-8-(2-Aminocyclohexylamino)-7-(2-difluoromethoxybenzyl)-3-methyl-3,7-dihydropurine-2,6-dione

[0424] HPLC-MS (Method A3): m/z=435 (M+1); R_(t)=3.30 min.

Example 37 General Procedure (D)

[0425] (±)Cis-8-(2-Aminocyclohexylamino)-7-(2-difluoromethoxybenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione

[0426] HPLC-MS (Method A3): m/z=448 (M+1); R_(t)=3.30 min.

Example 38 General Procedure (C)

[0427]8-(2-(S)-Aminocyclohexyl-(S)-amino)-1,3-dimethyl-7-(2-trifluoromethylbenzyl)-3,7-dihydropurine-2,6-dione

[0428]¹H NMR (MeOH-d4): δ 7.72 (m, 1H), 7.49 (m, 3H), 6.73 (d, 1H), 5.63(dd, 2H), 3.98 (m, 1H), 3.54 (s, 3H), 3.16 (m, 4H), 1.22-2.23 (m, 1 OH),HPLC-MS (Method B1) m/z=451 (M+1); R_(t)=2.16 min

Example 39 General Procedure (C)

[0429] (±) Cis8-(2-Aminocyclohexylamino)-1,3-dimethyl-7-(2-trifluoromethylbenzyl)-3,7-dihydropurine-2,6-dione

[0430]¹H NMR (MeOH-d4): δ 7.62 (d, 4H), 6.76 (m, 1H), 5.84 (d, 1H), 5.61(d, 1H), 4.39 (m, 1H), 3.73 (m, 1H), 3.52 (s, 3H), 3.20 (s, 3H), 1.64(m, 1 OH). HPLC-MS (Method B1) m/z=451 (M+1); R_(t)=4.09 min

Example 40 General Procedure (C)

[0431]8-(2-(S)-Aminocyclohexyl-(S)-amino)-7-(2-bromobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione

Example 41 General Procedure (C)

[0432] (±) Cis8-(2-Aminocyclohexylamino)-7-(2-bromobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione

[0433]¹H NMR (MeOH-d4): δ 7.62 (d, 1H), 7.22 (m, 2H), 6.71 (d, 1H), 5.51(dd, 2H), 4.36 (m, 1H), 3.74 (m, 1H), 3.51 (s, 3H), 3.19 (s, 3H), 1.62(m, 9H). HPLC-MS (Method B1) m/z=462 (M+1); R_(t)=2.19 min

Example 42 General Procedure (D)

[0434] (±)Cis-8-(2-Aminocyclohexylamino)-7-(2-bromobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione

[0435] HPLC-MS (Method A3): m/z=461 (M+1); R_(t)=3.60 min.

Example 43 General Procedure (D)

[0436] (±)Cis-8-(2-Aminocyclohexylamino)-3-benzyl-7-(2-chlorobenzyl)-3,7-dihydropurine-2,6-dione

[0437] HPLC-MS (Method A3): m/z=478 (M+1); R_(t)=3.60 min.

Example 44 General Procedure (E)

[0438] (±)Cis-2-[8-(2-Aminocyclohexylamino)-7-(2-cyanobenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-1-ylmethyl]benzonitrile

[0439]¹H NMR (DMSO-d₆): δ 7.89 (d, 1H); 7.79 (d, 1H); 7.64 (t, 1H); 7.57(t, 1H); 7.47 (t, 1H); 7.41 (t, 1H); 7.13 (d, 1H); 6.84 (d, 1H); 5.65(s, 2H); 5.11 (s, 2H); 3.92 (m, 1H); 3.41 (s, 3H); 3.12 (m, 1H);1.80-1.15 (m, 8H). HPLC-MS (Method B1) m/z=509 (M+1) 531 (M+23);R_(t)=2.527 min.

Example 45 General Procedure (E)

[0440]8-(2-(S)-Aminocyclohexyl-(S)-amino)-7-(2-chlorobenzyl)-3-methyl-1-(2-oxo-2-phenylethyl)-3,7-dihydropurine-2,6-dione

[0441]¹H NMR (DMSO-d₆): δ 8.03-7.77 (m, 4H); 7.68-7.55 (m, 1H);7.53-7.36 (m, 3H); 7.29-7.09 (m, 3H); 6.59-6.46 (m, 1H); 5.45-5.23 (1H);5.23-5.08 (m, 3H); 3.88-3.64 (m, 2H); 3.38 (s, 3H); 3.05-2.86 (m, 1H);2.03-1.79 (m, 2H); 1.73-1.52 (m, 2H). HPLC-MS (Method B1) m/z=521(M+1);R_(t)=2.967 min.

Example 46 General Procedure (D)

[0442] (±)Cis-8-(2-Aminocyclohexylamino)-3-benzyl-7-(2-bromobenzyl)-3,7-dihydropurine-2,6-dione

[0443] HPLC-MS (Method A3): m/z=523 (M+1); R_(t)=4.00 min.

Example 47 General Procedure (B))

[0444] (±)Cis-8-(2-Aminocyclohexylamino)-7-(2-chlorobenzyl)-3-methyl-1-(2-oxo-2-thiophen-3-yl-ethyl)-3,7-dihydropurine-2,6-dione

[0445] HPLC-MS (Method A3): m/z=528 (M+1); R_(t)=4.20 min.

Example 48 General Procedure (B)

[0446]2-(8-(2-(S)-Aminocyclohexyl-(S)-amino)-1-[2-(3-fluorophenyl)-2-oxoethyl]-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile

[0447] HPLC-MS (Method A3): m/z=530 (M+1); R_(t)=4.00 min.

Example 49 General Procedure (E)

[0448]8-(2-(S)-Aminocyclohexyl-(S)-amino)-7-(2-bromobenzyl)-3-methyl-1-(2-oxo-2-phenylethyl)-3,7-dihydropurine-2,6-dione

[0449] HPLC-MS (Method B1) m/z=565 (M+1); R_(t)=3,23 min.

Example 50 General Procedure (B)

[0450]8-(2-(S)-Aminocyclohexyl-(S)-amino)-7-(2-bromobenzyl)-3-methyl-1-(2-oxo-2-thiophen-3-yl-ethyl)-3,7-dihydropurine-2,6-dione

[0451]¹H NMR (DMSO-d₆): δ 8.64-8.68 (m, 1H), 7.64-7.72 (m, 2H),7.48-7.54 (d, 1H), 7.28-7.36 (t, 1H), 7.18-7.26 (t, 1H), 6.48-6.52 (d,1H), 6.35 (s, 2H), 5.14 (s, 2H), 1.06-2.00 (m, 8H). HPLC-MS (Method B2)m/z=573 (M+1); R_(t)=5.00 min.

Example 51 General Procedure (B)

[0452] (±)Cis-8-(2-Aminocyclohexylamino)-7-(2-bromobenzyl)-3-methyl-1-(2-oxo-2-thiophen-3-yl-ethyl)-3,7-dihydropurine-2,6-dione

[0453] HPLC-MS (Method A3): m/z=572 (M+1); R_(t)=4.20 min.

Example 52

[0454]8-(2-(S)-Aminocyclohexyl-(S)-amino)-7-(2-bromobenzyl)-3-methyl-1-phenethyl-3,7-dihydropurine-2,6-dione.TFA

[0455] Step A:8-Bromo-7-(2-bromobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione (52A)

[0456] 8-Bromo-3-methyl-3,7-dihydropurine-2,6-dione (5 g, 20.4 mmol),dimethyl formamide (150 ml), 2-bromobenzylbromid (5.35 g, 21.4 mmol),and diisopropylethylamine (7 ml) were reacted and purified as describedin example 29, step A, to afford compound 52A as white crystals.

[0457] Yield: 7 g (83%).

[0458] HPLC-MS (Method B2): m/z=415 (M+1), R_(t)=3.129 min.

[0459] Step B:8-Bromo-7-(2-bromobenzyl)-3-methyl-1-phenethyl-3,7-dihydropurine-2,6-dione(52B)

[0460] 8-Bromo-7-(2-bromobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione(52A) (2,0 g, 4.8 mmol), dimethyl formamide (50 ml), 2-bromoethylbenzen(1.92 g, 9.7 mmol), and potassium carbonate (2,0 g, 14.5 mmol) werestirred at 50° C. for 20 hours. The mixture was poured into water (250ml) and ethyl acetate (20 ml). The precipitate was collected byfiltration to afford compound 52B as white crystals.

[0461] Yield: 2.32 g (93%).

[0462] HPLC-MS (Method B2): m/z=519 (M+1), R_(t)=5.06 min.

[0463] Step C:8-(2-(S)-Aminocyclohexyl-(S)-amino)-7-(2-bromobenzyl)-3-methyl-1-phenethyl-3,7-dihydropurine-2,6-dione.TFA (52)

[0464]8-Bromo-7-(2-bromobenzyl)-3-methyl-1-phenethyl-3,7-dihydropurine-2,6-dione(52B) (250 mg, 0.48 mmol) and (1S, 2S)-(+)-1,2-diamino-cyclohexan (277mg, 2.41 mmol) were dissolved in DMSO (10 ml). The mixture was stirredat 65° C. for two days, and then poured into water (100 ml) anddichloromethane (100 ml). The layers were separated and the aqueouslayer was extracted with dichloromethane (2×100 ml). The combinedorganic layers were washed with water, dried with sodium sulphate,filtered and evaporated. The crude product was redissolved indichloromethane (3 ml) and concentrated trifluoroacetic acid (½ ml) wasadded. The solvent was evaporated and the remaining was purified bypreparative HPLC (method A1, R_(t)=9.59 min.) to give the title compoundas yellow crystals.

[0465] Yield: 77 mg (30%).

[0466] HPLC-MS (Method B2): m/z=533 (M+2), R_(t)=3.24 min.

Example 53

[0467]8-(2-(S)-Aminocyclohexyl-(S)-amino)-7-(2-chlorobenzyl)-3-methyl-1-phenethyl-3,7-dihydropurine-2,6-dione.TFA

[0468] Step A:8-Bromo-7-(2-chlorobenzyl)-3-methyl-3.7-dihydropurine-2,6-dione. (53A)

[0469] 8-Bromo-3-methyl-3,7-dihydropurine-2,6-dione (5 g, 20.4 mmol),dimethyl formamide (150 ml), 2-chlorobenzylbromid (2.8 ml, 21.6 mmol),and diisopropylethylamine (7 ml) were reacted and purified as describedin example 29, step A, to afford compound 53A as white crystals.

[0470] Yield: 6.6 g (88%).

[0471] HPLC-MS (Method B2): m/z=371 (M+1), R_(t)=3.031 min.

[0472] Step B:8-Bromo-7-(2-chlorobenzyl)-3-methyl-1-phenethyl-3,7-dihydropurine-2,6-dione(53B)

[0473] 8-Bromo-7-(2-chlorobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione(53A) (1.5 g, 4.05 mmol), dimethyl formamide (50 ml), 2-bromoethylbenzen(1.48 y, 8.0 mmol), and potassium carbonate (1.68 g, 12.15 mmol) werestirred at 50° C. for 20 hours. The mixture was poured into water (250ml) and ethyl acetate (20 ml). The precipitate was collected byfiltration to afford compound 53B as white crystals.

[0474] Yield: 1,43 g (76%).

[0475] HPLC-MS (Method B2): m/z=475 (M+2), R_(t)=4.98 min.

[0476] Step C:8-(2-(S)-Aminocyclohexyl-(S)-amino)-7-(2-chlorobenzyl)-3-methyl-1-phenethyl-3,7-dihydropurine-2,6-dione.TFA (53)

[0477]8-Bromo-7-(2-chlorobenzyl)-3-methyl-1-phenethyl-3,7-dihydropurine-2,6-dione(53B) (250 mg, 0.528 mmol) and (1S,2S)-(+)-1,2-diamino-cyclohexan (301mg, 2.64 mmol) were reacted and purified as described in example 52,step C, to give the title compound as white crystals.

[0478] Yield: 38 mg (12%).

[0479] Prep. HPLC (method A1) R_(t)=9.53 min.

[0480] HPLC-MS (Method B2): m/z=507 (M+), Rt=3.32 min.

Example 54

[0481]2-[8-(2-(S)-Aminocyclohexyl-(S)-amino)-7-(2-chlorobenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-1-ylmethyl]benzonitrile. TFA

[0482] Step A:2-(8-Bromo-7-(2-chlorobenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-1-ylmethyl)benzonitrile(54A)

[0483] 8-Bromo-7-(2-chlorobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione(53A) (1.5 g, 4.05 mmol), dimethyl formamide (50 ml), alphabromo-O-tolunitrile (1.59 g, 8.11 mmol), and potassium carbonate (1.68g, 12.15 mmol) were stirred at 50° C. for 20 hours. The mixture waspoured into water (250 ml) and ethyl acetate (20 ml). The precipitatewas collected by filtration to afford compound 54A as white crystals.

[0484] Yield: 1,66 g (85%).

[0485] HPLC-MS (Method B2): m/z=486 (M+2), Rt=4.428 min.

[0486] Step B:2-[8-(2-(S)-Aminocyclohexyl-(S)-amino)-7-(2-chlorobenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-1-ylmethyl]benzonitrile.TFA (54)

[0487]2-(8-Bromo-7-(2-chlorobenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-1-ylmethyl)benzonitrile(54A) (250 mg, 0.516 mmol) and (1S,2S)-(+)-1,2-diamino-cyclohexan (294mg, 2.58 mmol) were reacted and purified as described in example 52,step C, to give the title compound as yellow crystals.

[0488] Yield: 97 mg (30%).

[0489] HPLC-MS (Method B2): m/z=518 (M+), Rt=3.105 min.

What is claimed is:
 1. A compound of formula II

A is C₂-C₆ alkylene; C₂-C₁₀ alkenylene; C₃-C₇ cycloalkylene; C₃-C₇cycloheteroalkylene; arylene; heteroarylene; C₁-C₂ alkylene-arylene;arylene-C₁-C₂ alkylene; or C₁-C₂ alkylene-arylene-C₁-C₂ alkylene,wherein each alkylene, alkenylene, cycloalkylene, cycloheteroalkylene,arylene, or heteroarylene is optionally substituted with one or more R³independently; R¹ is aryl optionally substituted with one or more R²independently, or heteroaryl optionally substituted with one or more R²independently; R² is H; C₁-C₇ alkyl; C₂-C₇ alkenyl; C₂-C₇ alkynyl; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; —NHCOR³; —NHSO₂R³; —SR³; —SOR³;—SO₂R³; —OCOR³; —CO₂R⁴; —CON(R⁴)₂; —CSN(R⁴)₂; —NHCON(R⁴)₂; —NHCSN(R⁴)₂;—NHCONNH₂; —SO₂N(R⁴)₂; —OR⁴; cyano; —CF₃; nitro; or halogen, whereineach alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl isoptionally substituted with one or more R³ independently; R³ is C₁-C₁₀alkyl; C₂-C₁₀ alkenyl; C₂-C₁₀ alkynyl; C₃-C₇ cycloalkyl; aryl;heteroaryl; OR¹⁰; N(R¹⁰)₂; or SR¹⁰, wherein each alkyl, alkenyl,alkynyl, cycloalkyl, aryl and heteroaryl is optionally substituted withone or more R¹⁰ independently; R⁴ is H; C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl;C₂-C₁₀ alkynyl; C₃-C₇ cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl;aryl-C₁-C₅ alkylene; heteroaryl; heteroaryl-C₁-C₅ alkylene, —CF₃ or—CHF₂, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloheteroalkyl, aryl, aryl-C₁-C₅ alkylene, heteroaryl, andheteroaryl-C₁-C₅ alkylene is optionally substituted with one or more R¹⁰independently; R⁵ is H; C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₂-C₁₀ alkynyl;C₃-C₇ cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; heteroaryl; —OR⁷;aryl-C₁-C₅ alkylene; heteroaryl-C₁-C₅ alkylene; —C₁-C₅-alkyl-C(═O)-aryl;—C₁-C₅-alkyl-C(═O)-heteroaryl; or —[(CH₂)₀-O]_(p)—C₁-C₅ alkyl, wherein oand p are 1-3 independently, and wherein each alkyl, alkenyl, alkynyl,cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, aryl-C₁-C₅ alkylene,—C₁-C₅-alkyl-C(═O)-aryl, —C₁-C₅-alkyl-C(═O)-heteroaryl andheteroaryl-C₁-C₅ alkylene is optionally substituted with one or more R⁷independently; R⁶ is H; C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₂-C₁₀ alkynyl;C₃-C₇ cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; heteroaryl; aryl-C₁-C₅alkylene; heteroaryl-C₁-C₅ alkylene; or C₃-C₇ cycloheteroalkyl-C₁-C₅alkylene, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloheteroalkyl, C₃-C₇ cycloheteroalkyl-C₁-C₅ alkylene, aryl,heteroaryl, aryl-C₁-C₅ alkylene, and heteroaryl-C₁-C₅ alkylene isoptionally substituted with one or more R¹⁰ independently; R⁷ is H; ═O;C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₂-C₁₀ alkynyl; C₃-C₇ cycloalkyl; C₃-C₇cycloheteroalkyl; aryl; heteroaryl; OR¹⁰; N(R¹⁰)₂; SR¹⁰; cyano; hydroxy;halogen; —CF₃; —CCl₃; —OCF₃; or —OCH₃ wherein each alkyl, alkenyl,alkynyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl isoptionally substituted with one or more R¹⁰ independently; R⁸ is H;C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₂-C₁₀ alkynyl; C₃-C₇ cycloalkyl; C₃-C₇cycloheteroalkyl; aryl; heteroaryl; OR¹⁰; N(R¹⁰)₂; or SR¹⁰, wherein eachalkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, andheteroaryl is optionally substituted with one or more R¹⁰ independently;R⁹ is H; C₁-C₁₀ alkyl optionally substituted with one or more R⁸independently; or halogen; R¹⁰ is H; —CF₃; —CCl₃; —OCF₃; —OCH₃; cyano;halogen; —OH, —COCH₃; —CONH₂; —CONHCH₃; —CON(CH₃)₂; —NO₂; —SO₂NH₂; or—SO₂N(CH₃)₂; if two R⁴ or two R¹⁰ are attached to the same nitrogen theymay be connected to form a 3- to 7-membered ring; R¹¹ is H or C₁-C₆alkyl optionally substituted with one or more R³ independently; R¹² isH; C₁-C₆ alkyl optionally substituted with one or more R³ independently;or If A is C₃-C₇ cycloalkylene or C₃-C₇ cycloheteroalkylene R¹² may be avalence bond between the nitrogen to which R¹² is attached and one ofthe atoms in the cycloalkylene or cycloheteroalkylene; or a salt thereofwith a pharmaceutically acceptable acid or base.
 2. A compound accordingto claim 1, wherein A is C₂-C₆ alkylene; C₂-C₁₀ alkenylene; C₃-C₇cycloalkylene; C₃-C₇ cycloheteroalkylene; or arylene, wherein eachalkylene, alkenylene, cycloalkylene, cycloheteroalkylene, or arylene isoptionally substituted with one or more R³ independently.
 3. A compoundaccording to claim 2, wherein A is C₂-C₆ alkylene; C₂-C₁₀ alkenylene;C₃-C₇ cycloalkylene; C₃-C₇ cycloheteroalkylene; arylene; heteroarylene;C₁-C₂ alkylene-arylene; arylene-C₁-C₂ alkylene; or C₁-C₂alkylene-arylene-C₁-C₂ alkylene, wherein each alkylene, alkenylene,cycloalkylene, cycloheteroalkylene, arylene, or heteroarylene isoptionally substituted with one or more R³ independently; R¹ is aryloptionally substituted with one or more R² independently or heteroaryloptionally substituted with one or more R² independently; R² is H; C₁-C₇alkyl; C₂-C₇ alkenyl; C₂-C₇ alkynyl; C₃-C₇ cycloalkyl; C₃-C₇cycloheteroalkyl; —NHCOR³; —NHSO₂R³; —SR³; —SOR³; —SO₂R³; —OCOR³;—CO₂R⁴; —CON(R⁴)₂; —CSN(R⁴)₂; —NHCON(R⁴)₂; —NHCSN(R⁴)₂; —NHCONNH₂;—SO₂N(R⁴)₂; —OR⁴; cyano; nitro; or halogen, wherein each alkyl, alkenyl,alkynyl, cycloalkyl and cycloheteroalkyl is optionally substituted withone or more R³ independently; R³ is C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₂-C₁₀alkynyl; C₃-C₇ cycloalkyl; aryl; heteroaryl; OR¹⁰; N(R¹⁰)₂; or SR¹⁰,wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl isoptionally substituted with one or more R¹⁰ independently; R⁴ is H;C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₂-C₁₀ alkynyl; C₃-C₇ cycloalkyl; C₃-C₇cycloheteroalkyl; aryl; aryl-C₁-C₅ alkylene; heteroaryl; orheteroaryl-C₁-C₅ alkylene, wherein each alkyl, alkenyl, alkynyl,cycloalkyl, cycloheteroalkyl, aryl, aryl-C₁-C₅ alkylene, heteroaryl, andheteroaryl-C₁-C₅ alkylene is optionally substituted with one or more R¹⁰independently; R⁵ is H; C₁-C₁₀alkyl; C₂-C₁₀alkenyl; C₂-C₁₀ alkynyl;C₃-C₇ cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; heteroaryl; —OR⁷; or—[(CH₂)_(o)—O]_(p)—C₁-C₅ alkyl, wherein o and p are 1-3 independently,and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl,aryl, and heteroaryl is optionally substituted with one or more R⁷independently; R⁶ is H; C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₂-C₁₀ alkynyl;C₃-C₇ cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; heteroaryl; aryl-C₁-C₅alkylene; heteroaryl-C₁-C₅ alkylene; or C₃-C₇ cycloheteroalkyl-C₁-C₅alkylene, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloheteroalkyl, C₃-C₇ cycloheteroalkyl-C₁-C₅ alkylene, aryl,aryl-C₁-C₅ alkylene, heteroaryl, aryl-C₁-Cs alkylene, andheteroaryl-C₁-C₅ alkylene is optionally substituted with one or more R¹⁰independently; R⁷ is H; ═O; C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl; C₂-C₁₀alkynyl; C₃-C₇ cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; heteroaryl,OR¹⁰; N(R¹⁰)₂; SR¹⁰; cyano; hydroxy; halogen; —CF₃; —CCl₃; —OCF₃; or—OCH₃ wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloheteroalkyl, aryl, and heteroaryl is optionally substituted withone or more R¹⁰ independently; R⁸ is H; C₁-C₁₀ alkyl; C₂-C₁₀ alkenyl;C₂-C₁₀ alkynyl; C₃-C₇ cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl;heteroaryl, OR¹⁰; N(R¹⁰)₂; or SR¹⁰, wherein each alkyl, alkenyl,alkynyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl isoptionally substituted with one or more R¹⁰ independently; R⁹ is H;C₁-C₁₀ alkyl optionally substituted with one or more R⁸ independently;or halogen; R¹⁰ is H; —CF₃; —CCl₃; —OCF₃; —OCH₃; cyano; halogen; —OH,—COCH₃; —CONH₂; —CONHCH₃; —CON(CH₃)₂; —NO₂; —SO₂NH₂; or —SO₂N(CH₃)₂; iftwo R⁴ or two R¹⁰ are attached to the same nitrogen they may beconnected to form a 3- to 7-membered ring; R¹¹ is H or C₁-C₆ alkyloptionally substituted with one or more R³ independently; R¹² is H;C₁-C₆ alkyl optionally substituted with one or more R³ independently; orIf A is C₃-C₇ cycloalkylene or C₃-C₇ cycloheteroalkylene R¹² may be avalence bond between the nitrogen to which R¹² is attached and one ofthe atoms in the cycloalkylene or cycloheteroalkylene; or a salt thereofwith a pharmaceutically acceptable acid or base.
 4. A compound accordingto claim 2, wherein A is C₃-C₇ cycloalkylene optionally substituted withone or more R³ independently.
 5. A compound according to claim 4,wherein A is cyclohexylene or cycloheptylene, each optionallysubstituted with one or more R³ independently.
 6. A compound accordingto claim 5, wherein A is cyclohexylene optionally substituted with oneor more R³ independently.
 7. A compound according to claim 5, wherein Ais cyclohexylene or cycloheptylene.
 8. A compound according to claim 7,wherein A is cyclohexylene.
 9. A compound according to claim 7, whereinA is


10. A compound according to claim 1, wherein R¹ is aryl optionallysubstituted with one or more R² independently.
 11. A compound accordingto claim 10, wherein R¹ is phenyl optionally substituted with one ormore R² independently.
 12. A compound according to claim 1, wherein R₂is C₁-C₇ alkyl; C₂-C₇ alkynyl; —OR⁴; cyano; —CF₃; or halogen, whereineach alkyl and alkynyl is optionally substituted with one or more R³independently.
 13. A compound according to claim 12, wherein R₂ is C₁-C₇alkyl; C₂-C₇ alkynyl; cyano; —CF₃; or halogen.
 14. A compound accordingto claim 13, wherein R₂ is cyano, —CF₃ or halogen.
 15. A compoundaccording to claim 1, wherein R₂ is C₁-C₇ alkyl; C₂-C₇ alkynyl; cyano;or halogen, wherein each alkyl and alkynyl is optionally substitutedwith one or more R³ independently.
 16. A compound according to claim 15,wherein R₂ is C₁-C₇ alkyl; C₂-C₇ alkynyl; cyano; or halogen.
 17. Acompound according to claim 16, wherein R₂ is halogen.
 18. A compoundaccording to claim 1, wherein R³ is C₁-C₁₀ alkyl or aryl, wherein eachalkyl or aryl is substituted with one or more R¹⁰ independently.
 19. Acompound according to claim 18, wherein R³ is C₁-C₁₀ alkyl or aryl. 20.A compound according to claim 19, wherein R³ is methyl or phenyl.
 21. Acompound according to claim 1, wherein R⁴ is H; C₁-C₁₀ alkyl, —CHF₂, oraryl, wherein each alkyl or aryl is substituted with one or more R¹⁰independently.
 22. A compound according to claim 21, wherein R⁴ is H;C₁-C₁₀ alkyl, —CHF₂, or aryl.
 23. A compound according to claim 22,wherein R⁴ is H, —CHF₂, methyl or phenyl.
 24. A compound according toclaim 1, wherein R⁴ is H; C₁-C₁₀ alkyl or aryl, wherein each alkyl oraryl is substituted with one or more R¹⁰ independently.
 25. A compoundaccording to claim 24, wherein R⁴ is H; C₁-C₁₀ alkyl or aryl.
 26. Acompound according to claim 25, wherein R⁴ is H, methyl or phenyl.
 27. Acompound according to claim 1, wherein R⁵ is H; C₁-C₁₀ alkyl; aryl-C₁-C₅alkylene; —C₁-C₅-alkyl-C(═O)-aryl; or heteroaryl-C₁-C₅ alkylene, whereineach alkyl, aryl-C₁-C₅ alkylene and heteroaryl-C₁-C₅ alkylene isoptionally substituted with one or more R⁷ independently.
 28. A compoundaccording to claim 27, wherein R⁵ is H; C₁-C₁₀ alkyl optionallysubstituted with one or more R⁷ independently; —C₁-C₅-alkyl-C(═O)-aryloptionally substituted with one or more R⁷ independently or C₂-C₁₀alkenyl optionally substituted with one or more R⁷ independently.
 29. Acompound according to claim 28, wherein R⁵ is H, —C₁-C₅-alkyl-C(═O)-aryloptionally substituted with one or more R⁷ independently or C₁-C₁₀ alkyloptionally substituted with one or more R⁷ independently.
 30. A compoundaccording to claim 29, wherein R⁵ is H or —C₁-C₅-alkyl-C(═O)-phenyloptionally substituted with one or more R⁷ independently.
 31. A compoundaccording to claim 29, wherein R⁵ is methyl or ethyl optionallysubstituted with one or more R⁷ independently.
 32. A compound accordingto claim 1, wherein R⁵ is H; C₁-C₁₀ alkyl; aryl-C₁-C₅ alkylene; orheteroaryl-C₁-C₅ alkylene, wherein each alkyl, aryl-C₁-C₅ alkylene andheteroaryl-C₁-C₅ alkylene is optionally substituted with one or more R⁷independently.
 33. A compound according to claim 32, wherein R⁵ is H;C₁-C₁₀ alkyl optionally substituted with one or more R⁷ independently;or C₂-C₁₀ alkenyl optionally substituted with one or more R⁷independently.
 34. A compound according to claim 33, wherein R⁵ is H orC₁-C₁₀alkyl optionally substituted with one or more R⁷ independently.35. A compound according to claim 34, wherein R⁵ is H.
 36. A compoundaccording to claim 31, wherein R⁵ is methyl.
 37. A compound according toclaim 1, wherein R⁶ is C₁-C₁₀alkyl; aryl-C₁-C₅ alkylene; orheteroaryl-C₁-C₅ alkylene, wherein each alkyl, aryl-C₁-C₅ alkylene andheteroaryl-C₁-C₅ alkylene is optionally substituted with one or more R¹⁰independently.
 38. A compound according to claim 37, wherein R⁶ isC₁-C₁₀alkyl; aryl-C₁-C₅ alkylene; or heteroaryl-C₁-C₅ alkylene.
 39. Acompound according to claim 37, wherein R⁶ is C₁-C₁₀ alkyl optionallysubstituted with one or more R¹⁰ independently.
 40. A compound accordingto claim 39, wherein R⁶ is C₁-C₁₀ alkyl.
 41. A compound according toclaim 39, wherein R⁶ is methyl or ethyl optionally substituted with oneor more R¹⁰ independently.
 42. A compound according to claim 41, whereinR⁶ is methyl.
 43. A compound according to claim 1, wherein R⁷ is H; ═O;C₁-C₁₀ alkyl; C₃-C₇ cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl;heteroaryl, OR¹⁰; N(R¹⁰)₂; SR¹⁰, cyano; or halogen, wherein each alkyl,cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is optionallysubstituted with one or more R¹⁰ independently.
 44. A compound accordingto claim 43, wherein R⁷ is ═O; OR¹⁰; C₃-C₇ cycloalkyl; C₃-C₇cycloheteroalkyl; aryl; heteroaryl; cyano; or halogen, wherein eachcycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is optionallysubstituted with one or more R¹⁰ independently.
 45. A compound accordingto claim 44, wherein R⁷ is ═O; OR¹⁰; cyano; halogen; C₃-C₇ cycloalkyloptionally substituted with one or more R¹⁰ independently or aryloptionally substituted with one or more R¹⁰ independently.
 46. Acompound according to claim 1, wherein R⁷ is H; ═O; C₁-C₁₀ alkyl; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; heteroaryl, OR¹⁰; N(R¹⁰)₂; orSR¹⁰, wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl, andheteroaryl is optionally substituted with one or more R¹⁰ independently.47. A compound according to claim 46, wherein R⁷ is ═O; C₃-C₇cycloalkyl; C₃-C₇ cycloheteroalkyl; aryl; or heteroaryl, wherein eachcycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is optionallysubstituted with one or more R¹⁰ independently.
 48. A compound accordingto claim 47, wherein R⁷ is ═O; C₃-C₇ cycloalkyl optionally substitutedwith one or more R¹⁰ independently or aryl optionally substituted withone or more R¹⁰ independently.
 49. A compound according to claim 48,wherein R⁷ is ═O or aryl optionally substituted with one or more R¹⁰independently.
 50. A compound according to claim 49, wherein R⁷ is ═O orphenyl optionally substituted by one or more R¹⁰ independently.
 51. Acompound according to claim 1, wherein R⁸ is aryl or heteroaryl, whereineach aryl and heteroaryl is optionally substituted with one or more R¹⁰independently.
 52. A compound according to claim 51, wherein R⁸ is arylor heteroaryl.
 53. A compound according to claim 52, wherein R⁸ isphenyl.
 54. A compound according to claim 1, wherein R⁹ is H; C₁-C₁₀alkyl; or halogen.
 55. A compound according claim 54, wherein R⁹ is H.56. A compound according to claim 1, wherein R¹⁰ is H; —CF₃; —OH; cyano;halogen; —OCF₃; or —OCH₃.
 57. A compound according to claim 56, whereinR¹⁰ is H; cyano; halogen; or —OCH₃.
 58. A compound according to claim 1,wherein R¹¹ is H.
 59. A compound according to claim 1, wherein R¹² is H.